Pharmacological Research 106 (2016) 27–36

Contents lists available at ScienceDirect

Pharmacological Research
journal homepage: www.elsevier.com/locate/yphrs

Review

Cisplatin resistance and opportunities for precision medicine

Lauren Amable ∗
National Institute on Minority Health and Health Disparities, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, United States

a r t i c l e i n f o a b s t r a c t

Article history: Cisplatin is one of the most commonly used chemotherapy drugs, treating a wide range of cancer
Received 28 December 2015 types. Unfortunately, many cancers initially respond to platinum treatment but when the tumor returns,
Accepted 1 January 2016 drug resistance frequently occurs. Resistance to cisplatin is attributed to three molecular mechanisms:
Available online 22 January 2016
increased DNA repair, altered cellular accumulation, and increased drug inactivation. The use of preci-
sion medicine to make informed decisions on a patient’s cisplatin resistance status and predicting the
Keywords:
tumor response would allow the clinician to tailor the chemotherapy program based on the biology of
Cisplatin resistance
the disease. In this review, key biomarkers of each molecular mechanism will be discussed along with
Nucleotide excision repair
ERCC1
the current clinical research. Additionally, known polymorphisms for each biomarker will be discussed
Copper transporters in relation to their influence on cisplatin resistance.
ABC transporters Published by Elsevier Ltd.
Glutathione

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2. Altered DNA repair . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.1. ERCC1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.2. Other NER genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3. Altered accumulation of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.1. Decreased cellular uptake of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.1.1. Copper transporters CTR1 and CTR2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.1.2. Organic cation transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.2. Increased cellular export of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.2.1. P-type ATPase transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3.2.2. ATP-binding cassette (ABC) transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4. Cytosolic inactivation of cisplatin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.1. Inactivation by glutathione conjugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.1.1. Glutathione-S-transferase Pi 1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.1.2. Glutathione-S-transferase Mu . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
4.2. Inactivation by metallothionein binding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Abbreviations: ABC, ATP-binding cassette; ASE-1, anti-sense ERCC1; ATP7A, ATPase copper-transporting alpha polypeptide; ATP7B, ATPase copper-transporting beta
polypeptide; CAST, T-cell receptor complex subunit CD3␧-associated signal transducer; CTR1, copper transporter 1; CTR2, copper transporter 2; ERCC1, excision repair
cross-complementation group 1 gene; GSH, glutathione; GST, glutathione-s-transferase; MRP, multidrug resistance associated protein; MT, metallothionein; NER, nucleotide
excision repair; NSCLC, non-small cell lung cancer; OCT, organic cation transporter; PCNA, proliferating cell nuclear antigen; Pol, polymerase; SLC, solute carrier; TFIIH,
transcription factor II H; UTR, untranslated region; XPA, xeroderma pigmentosum group A; XPB, xeroderma pigmentosum group B; XPD, xeroderma pigmentosum group D;
XPE, xeroderma pigmentosum group E; XPF, xeroderma pigmentosum group F; XPG, xeroderma pigmentosum group G.
∗ Corresponding author. Fax: +1 301 480 4490.
E-mail address: lauren.amable@nih.gov

http://dx.doi.org/10.1016/j.phrs.2016.01.001
1043-6618/Published by Elsevier Ltd.
28 L. Amable / Pharmacological Research 106 (2016) 27–36

1. Introduction The second issue associated with cisplatin treatment is resis-

Rosenberg et al., first discovered in Escherichia coli that the
byproducts from platinum electrode activity resulted in the inhibi-
tion of cell division [1,2]. Within 15 years, cisplatin was approved
for the treatment of cancer by the FDA. Cisplatin is one of the most
widely used anticancer drugs in North America and Europe [3],
treating a variety of cancers including: testicular, ovarian, non-
small cell lung cancer (NSCLC), head and neck cancer, bladder,
gastric, and other malignancies [4]. The main issue with obtaining
the optimum cisplatin cancer treatment is the significant interpa-
tient variability with outcome, efficacy, and toxicity.
There are two problems associated with cisplatin usage in the
clinic: toxicity and resistance. Cisplatin has a numerous toxicities
including renal damage, deafness, and peripheral neuropathy, thus
the overall efficacy of the drug could not be reached due to the side
effects. This has led to the development of cisplatin analogs that
would be clinically effective but without the toxicity. Carboplatin
and oxaliplatin (Fig. 1), are the most popular analogs and reached
FDA approval for usage. Interestingly, there is a variation in the can-
cers treated by the cisplatin analogs. Carboplatin is not as effective
in treating germ cell malignancies compared to cisplatin. Oxali-
platin is very effective for the treatment of colon cancer, a cancer
where cisplatin is not effective. Understanding the molecular basis
for the difference between these three compounds could provide
new insights and unlock novel mechanisms into how cancer cells
counteract the effects of DNA-damaging drugs. While the analogs
show hope for a better response with less toxicity the scope of this
review will not cover cisplatin analog resistance. For a review on
cisplatin analog resistance, the author directs the reader to a recent
review from Perego and Robert [5].
tance to therapy. Initially the tumor responds to cisplatin but then
the tumor comes back and is frequently refractory to further plat-
inum therapy. There are two forms of resistance found in the clinic:
innate and acquired. Innate resistance is resistance without out any
prior drug exposure. Acquired resistance is a result of drug expo-
sure. The differences between innate and acquired resistance are
not clear but it is generally thought that each operates through
different signaling pathways. This review will only focus on resis-
tance as a whole since discerning between the two requires further
studies.
In the clinic, the definition of whether a patient is sensitive or
resistant to cisplatin is generally as follows. If a patient is more than
two years from the last platinum dose, the patient is considered
sensitive. There is a greater than 70% likelihood that the patient
will respond to treatment with platinum-based therapy [6]. The
percentage of patients who will respond to cisplatin decreases with
the shortening of the disease free period. Patients who have disease
recurrence within the first months after the recent platinum dose
will have a low likelihood of treatment response with cisplatin and
are considered to have platinum resistant disease.
When cisplatin is transported into the cell, cisplatin has several
fates (Fig. 2). First, cisplatin can be exported from the cell using a
transmembrane transporter system. Second, cisplatin can be chem-
ically neutralized by binding sulfhydryl groups in proteins such as
glutathione or metallothioneins. Finally, cisplatin nonspecifically
reacts with a variety of subcellular components: proteins, RNA, and
DNA. RNA is most sensitive to react with cisplatin, followed by DNA,
and then protein. The primary and widely accepted mechanism of
action for cisplatin is the binding to cellular DNA, resulting in DNA-
platinum adducts. This prevents the cell from replicating its DNA

Fig. 1. Cisplatin and analogs.

Fig. 2. Cellular fate of cisplatin (Pt). Cisplatin crosses the cell membrane by passive diffusion or by transmembrane transporters. CTR1, CTR2, and OCT2 have been identified
as transporters that import cisplatin into the cell. Once inside the cell, cisplatin binds to DNA to cause DNA-platinum adducts. The damage is repaired by ERCC1 and members
of the NER pathway. Cisplatin is also inactivated by glutathione-s-transferase, which add a glutathione (GSH) to cisplatin. The conjugated cisplatin-GSH is then exported via
the MRP2 transporters. Cisplatin is also exported by ATP7A and ATP7B. Inactivation of cisplatin can also result from binding metallothionein proteins (MT).
 L. Amable / Pharmacological Research 106 (2016) 27–36 29

until the damage is repaired. If the cell cannot repair the DNA or
the damage is too severe, then the cell dies.
Resistance to cisplatin occurs by the following molecular mech-
anisms: altered DNA repair, altered cellular accumulation of drug,
and cytosolic inactivation of drug. The processes of resistance were
studied in L1210 mouse leukemia cells and human ovarian cancer
cells [7–10]. The observations were similar in both cell models: all
three components contributed to cisplatin resistance. There were
differences of each mechanism regarding the relative contribu-
tions. At low levels of cisplatin resistance, about 10–15 fold above
baseline, the primary mechanism of resistance was DNA repair.
Intermediate levels of resistance, up to 40–50 fold over baseline,
was due to reduced cellular cisplatin accumulation. At very high
levels of resistance, cytosolic inactivation of cisplatin was the pri-
mary mechanism. However, in many cell lines it has been observed
that more than one mechanism can be occurring.
The goal of precision medicine is to generate better responses
in the clinic. Making an informed decision on predicting the tumor
response to cisplatin as well as the type of resistance that is occur-
ring allows for tailoring the chemotherapy program based on the
biology of the disease. Here in this review, we will comprehen-
sively discuss the mechanisms of cisplatin resistance-altered DNA
repair, altered cellular accumulation, and drug inactivation. For
each mechanism, the most promising biomarkers identified so far
will be discussed and are summarized in Table 1. Polymorphisms
of each biomarker that correlate with cisplatin resistance from cur-
rent clinical studies will also be presented, and are summarized in
Table 2.

2. Altered DNA repair

Once inside the cell, cisplatin binds to DNA and forms adducts.
The primary form of DNA damage are N7-d(GpG) and N7-d(ApG)
intrastrand DNA-platinum adducts. These bulky adducts result
in substantial kinking of the DNA (12), which is recognized and
repaired by the nucleotide excision repair (NER) pathway, shown
in Fig. 3. In this pathway, which requires more than 30 proteins, the
DNA-platinum adduct is first recognized by XPE and XPC-DDB1/2.
The transcription factor II H (TFIIH) complex verifies the damage
and assembles the pre-incision complex: RPA, XPA, and XPG. The
DNA is then unwound by the XPB and XPD helicases. ERCC1-XPF
and XPG endonucleases create an excision several bases upstream
and downstream from the DNA-platinum adduct. This releases the
oligonucleotide containing the adduct. The gap is filled in by the
DNA repair synthesis complex containing RPA, RFC, PCNA, and Pol
␦/␧. In the final step, the DNA is ligated by DNA ligase I, thus com-
pleting the DNA repair. The balance of DNA damage and DNA repair
dictates death versus survival after cisplatin therapy [11]. Changes
in the ability to repair the DNA adducts results in changes in cis-
platin sensitivity.
2.1. ERCC1
ERCC1 is one of the most highly studied biomarkers for cisplatin
resistance to date. The DNA damage excision step is catalyzed by
the ERCC1-XPF dimer is the rate limiting step in the NER path-
way. High ERCC1 levels are associated with increased removal of
DNA-platinum adducts and results in increased resistance to cis-
platin [12]. There is a linear correlation of ERCC1 expression and
cisplatin sensitivity, with resistant cells expressing more ERCC1
compared to sensitive. It was first demonstrated in ovarian can-
cer that ERCC1 levels are increased in cancer tissue in comparison
to normal [13]. Even higher levels of ERCC1 mRNA are found in
patients with clinically resistant cancer. Lower levels are found
in patients that are clinically sensitive to platinum therapy. In
Fig. 3. Schematic of nucleotide excision repair (NER). DNA-platinum adducts are
removed by the NER pathway. First the DNA-platinum adduct is detected. Then
the damage is verified and the pre-incision complex is set up containing RPA, XPA,
and XPG. DNA is unwound by XPB and XPD. XPF-ERCC1 and XPG create incisions 5
and 3 from the damaged base. The oligonucleotide containing the damaged base is
removed. The gap is filled in by DNA repair synthesis complex: RPA, RFC, PCNA, and
Pol ␦/␧. Finally, the DNA is ligated.
another study comparing the six histologic types of ovarian cancer,
there is an upregulation of NER genes that correlates with cisplatin
resistance. Clear cell tumors are known to be the most chemore-
sistant to cisplatin, and they displayed the highest levels of ERCC1
[14]. The evaluation of ERCC1’s potential role as a cisplatin resis-
tance biomarker has been explored in other cancers. High ERCC1
levels that correlate with increased resistance to cisplatin have
been observed in: ovarian [15,16], NSCLC [15,17–23], nasopha-
ryngeal [24,25], esophageal [26], cervical [27,28], head and neck
squamous carcinoma [29,30], liver [31], osteosarcoma [32], lung
adenocarcinoma [33], advanced biliary tract adenocarcinoma [34],
mesothelioma [35], pulmonary adenocarcinoma [36], and gastric
[11]. Thus, the expression of ERCC1 makes an attractive biomarker
for cisplatin resistance since the increased expression has been
observed in a variety of cancer types.
There are two polymorphisms of ERCC1 that appear to have clin-
ical significance with sensitivity to cisplatin treatment. The first
polymorphism, rs11615, is located in codon 118, and codes for the
same amino acid-asparagine, was first described by Yu et al. [37,38].
A point to note for this polymorphism: there is a discrepancy in
the literature on whether the change is from C to T or T to C. The
reader should take caution in evaluating studies, as these alleles are
switched in some analyses. Here this review the rs11615 polymor-
phism is from C to T. The rs11615, or N118N, polymorphism was
originally thought to result in reduced levels of ERCC1 mRNA and
30 L. Amable / Pharmacological Research 106 (2016) 27–36

Table 1
Proteins associated with cisplatin resistance.

Protein Relationship to resistance Cancer References

NER
ERCC1 Increased expression Ovarian, NSCLC, nasopharyngeal, esophageal, [13–16], [15], [17–23], [24,25], [26], [27,28],
cervical, head and neck squamous carcinoma, [29,30], [31], [32], [33], [34], [35], [36], [11]
liver, osteosarcoma, lung adenocarcinoma,
biliary tract adenocarcinoma, mesothelioma,
pulmonary adenocarcinoma, gastric
XPA Increased expression Ovarian cancer [53,54]
XPB Increased expression Ovarian cancer [53,54]
XPF Increased expression Ovarian and colon cancer cell lines; head and [55–57]
neck carcinoma
XPD Increased expression NSCLC and glioma cell lines [58,59]

Cellular uptake
CTR1 Decreased expression Ovarian cancer, NSCLC [73–75]
CTR2 Increased expression Ovarian cancer [80,81]
OCT2 No change Ovarian cancer [83]
Decreased expression Gastric cancer [84]

Cellular export
ATP7A Increased expression NSCLC, ovarian cancer [87,89,90]
ATP7B Increased expression Gastric, hepatocellular, esophageal, oral, [93–101]
breast, endometrial, lung, ovarian cancer
MRP2 Increased expression Colorectal, esophageal, hepatocellular cancer [111–113]

Drug inactivation
GSTP1 Increased expression Ovarian cancer, head and neck carcinoma, [122–124]
NSCLC
No change Ovarian, cervical cancer [130–132]
MT Increased expression Esophageal, ovarian cancer [151,123]

Table 2
Gene polymorphisms associated with cisplatin resistance.

Gene Polymorphism Response to cisplatin Cancer Reference

NER
ERCC1 rs11615, N118N Increased response Ovarian cancer, colorectal, pancreatic, osteosarcoma and NSCLC [38,40,42–45]
Decreased response NSCLC [46,47]
C8092A Increased response NSCLC, esophageal [49,50]
Decreased response Nasopharyngeal, mesothelioma [51,35]
No relationship NSCLC [52]
XPD Asp312Asn Increased response NSCLC, osteosarcoma, pancreatic cancer [54,60,62,63]

Cellular uptake
CTR1 rs7851395, rs12686377 Increased response NSCLC [76]
OCT2 rs195854, rs186941 Increased response NSCLC [85]

Cellular export
MRP2 C-24T Increased response NSCLC [116,117]

Drug inactivation
GSTM1 rs10431718 Increased response Lymphoblastoid cell lines [143]
Null allele Increased response NSCLC [144]

protein, as the codon is an infrequently used codon [37–39]. A clini-
cal molecular correlative study in ovarian cancer was confirmatory
[40] but in another recent study it was shown to not change the
expression or function of ERCC1 but rather may be linked to other
causative variants [41]. There are conflicting data as to whether or
not this polymorphism determines sensitivity to cisplatin. In ovar-
ian cancer, the T allele was associated with an increased response
to cisplatin therapy [40]. This was also observed in colorectal can-
cer [42], pancreatic cancer [43], osteosarcoma [44] and NSCLC [45].
Yet in another study, the C allele was associated with a higher
response rate to cisplatin, progression free survival, and overall
survival [46,47]. Thus two opposite results have been observed.
The second ERCC1 polymorphism relating to cisplatin sensitivity
is C8092A. This polymorphism was first identified in gliomas and is
located in the 3 UTR of ERCC1 [48]. The A allele is thought to result
in decreased mRNA stability of ERCC1. This polymorphism results in
an A substitution in two additional genes, nucleolar protein ASE-1
and t-cell receptor complex subunit CD3␧-associated signal trans-
ducer (CAST) [48]. Thus the exact role of this polymorphism is not
fully understood as these genes may have an effect that has not been
evaluated. Studies evaluating the C8092A polymorphism are few
and are additionally associated with conflicting data. The clinical
implication of the C8092A ERCC1 polymorphism has been studied
in lung [49] and esophageal cancer [50] and both studies demon-
strated the A polymorphism results in increased cisplatin response.
There is also conflicting data as to the A allele and clinical resistance
to platinum-based therapy. In a nasopharyngeal cancer study, the
A allele of C8092A was associated with an increased risk of dis-
ease progression with patients on cisplatin-based chemotherapy
[51]. In a malignant pleural mesothelioma study, the A polymor-
phism of C8092A was associated with a shorter progression free
survival [35]. Yet, in a meta-analysis of 39 NSCLC studies, there
was no relationship of survival and sensitivity to treatment with
platinum-based chemotherapy [52].
2.2. Other NER genes
While the majority of the studies have focused on ERCC1, there
are several studies that suggest other NER genes are involved in
cisplatin resistance. Dabholkar et al., showed that other NER genes
 L. Amable / Pharmacological Research 106 (2016) 27–36
are additionally upregulated in patients who responded to cisplatin
therapy [53]. XPA, which is part of the pre-incision complex, and
XPB, a helicase, displayed increased expression in cisplatin resis-
tant ovarian cancer tumors [53,54]. However, this has not been
explored further in other clinical studies. Neither XPA nor XPB
polymorphisms have been discovered that correlate with cisplatin
resistance.
It is logical to think that XPF would be an additional cisplatin
resistance marker since it is dimerizes with ERCC1 to catalyze the
incision of the damaged DNA strand. However, XPF has been over-
looked in many studies as to whether or not it is a valid biomarker
for cisplatin resistance. In ovarian and colon cancer cell lines, the
increased protein expression of XPF was correlated with increased
cisplatin resistance [55]. There have only been two clinical stud-
ies that have examined XPF [56,57]. Both studies examined head
and neck cancer and increased XPF expression was correlated with
cisplatin resistance. Vaezi et al. went on further to examine XPF
polymorphisms, however the four polymorphisms they identified
showed marginal association with treatment failure [57]. Further
studies examining the role of XPF in other cancers are needed.
The helicase XPD was additionally identified to have a strong
correlation between increased expression and cisplatin resistance
in NSCLC and glioma cell lines [58,59]. The expression of XPD has
not been evaluated in clinical samples. The majority of the clinical
studies have examined the effects of XPD polymorphisms on cis-
platin resistance. Two polymorphisms in XPD have been identified,
Asp312Asn and Lys751Gln, both result in decreased DNA repair
capacity. Both polymorphisms were found to be potential biomark-
ers for clinical outcome in osteosarcomas and lung cancers treated
with cisplatin [44,60]. The Asp312Asn polymorphism was associ-
ated with a better survival in osteosarcoma patients treated with
cisplatin [61]. The Lys751Gln polymorphism was associated with
longer progression free survival in pancreatic and NSCLC [62,63].
3. Altered accumulation of cisplatin
The second mechanism of cisplatin resistance is altered cellu-
lar accumulation of cisplatin. It has long been noted that cisplatin
resistant cells tend to exhibit decreased levels of cisplatin [64]. Tis-
sue platinum concentrations are correlated with percent reduction
of the tumor, meaning reduced tissue platinum concentrations are
associated with resistance [65]. Altered accumulation of cisplatin is
the result of two independent cellular pathways: decreased uptake
or increased export.
3.1. Decreased cellular uptake of cisplatin
Cisplatin has a simple chemistry, the core is a single platinum
metal bound to two amino groups and two chlorides (Fig. 1). At
physiologic pH, the chlorides of cisplatin are replaced with OH
molecules, resulting in a neutral charge. This it makes it possi-
ble for diffusion across the cellular membrane, flowing from the
high concentration of cisplatin outside to the lower concentration
inside the cell. Thus, cisplatin uptake was first thought to be via
passive diffusion as uptake was not saturated against time or drug
concentrations, up to 3 mM [66,67]. However, it was discovered
that cisplatin mostly enters the cell by membrane transporters.
This would explain why it has been observed that low levels of
transporters correlate with decreased levels of cellular cisplatin.
Cisplatin uptake is performed by the copper transporters CTR1 and
CTR2, as well as the organic cation transporter (OCT) family [68].
3.1.1. Copper transporters CTR1 and CTR2
Copper transporter protein 1 (CTR1) was shown to be one of
the primary cisplatin transporters. It was first discovered in yeast,
noting that knocking down CTR1 resulted in reduced uptake in
31
cisplatin [69]. CTR1 primarily transports copper, which is impor-
tant in a variety of biological functions within a cell. Interestingly,
resistance to cisplatin is accompanied by resistance to copper and
cisplatin resistant cells display reduced levels of copper [70]. Cis-
platin resistant cells show decreased levels of CTR1 mRNA and
decreased cisplatin uptake [71,72]. In the clinic, CTR1 has been eval-
uated in two cancer types, ovarian and lung, both resulting in the
same observation. In ovarian cancer patients treated with cisplatin
chemotherapy, high levels of CTR1 mRNA expression was corre-
lated with increased disease free survival [73]. In NSCLC, the same
pattern has emerged, high CTR1 protein levels were associated with
a favorable cisplatin response [74,75].
Only one study has examined the relationship of CTR1
polymorphisms with cisplatin resistance. Xu et al. found two
polymorphisms in CTR1 that correlate with platinum resistance
and survival: rs7851395 and rs12686377 [76]. These two poly-
morphisms are located in the intron region of CTR1 and are
hypothesized to play a role in the epigenetic regulation of CTR1.
Currently, it is not known what effect these polymorphisms have
on the function of CTR1, as this article was the first to describe them.
Cisplatin is also transported by another copper transporter,
CTR2. While CTR2 is in the same family as CTR1, they only share
a 33% homology on the protein level [77]. CTR2 is found on the
cellular membrane like CTR1, but it is also found on intracellular
organelle membranes and may have alternative cellular functions
[78]. The opposite effect has been observed with CTR2 in terms of
its correlation with cisplatin resistance. Unlike CTR1, knockdown
of CTR2 in cells results in increased uptake, increased cytotoxicity,
and increased sensitivity to cisplatin [79]. In two clinical studies,
lower levels of CTR2 are associated with a better outcome to cis-
platin therapy [80,81]. Interestingly, it has been suggested that the
CTR1/CTR2 ratio may be a useful biomarker for identifying tumors
which may be more sensitive to cisplatin than on one of the trans-
porters alone [81]. No CTR2 polymorphisms have been identified
to influence cisplatin sensitivity.
3.1.2. Organic cation transporters
The solute carrier (SLC) transporter family, specifically the SLC22
family members, also transport cisplatin into cells. Members of
this family, OCT1, OCT2, and OCT3, have been shown to uptake
platinum-compounds into cells, but each transporter varies in the
expression and substrate [68]. OCT1 has been indicated to trans-
port cisplatin, however the evidence is weak [68]. OCT1 transports
the cisplatin analogs carboplatin and oxaliplatin. OCT3 is known to
primarily transport oxaliplatin.
Cisplatin is primarily transported by OCT2, or SLC22A2, and this
transporter is found in the kidney. OCT2 transfection into cells
results in increased cellular levels of cisplatin [82]. There is not
a lot of clinical studies examining OCT2’s role in cisplatin resis-
tance, primarily due to the fact it is expressed in the kidney. In the
NCI-60 panel of cancer cell lines, OCT2 was the most frequently
expressed gene but its expression in clinical ovarian cancer spec-
imens was low and did not correlate with the treatment outcome
of a platinum-based regimen [83]. In one gastric cancer study,
higher levels of OCT2 were observed in responders to cisplatin-
based neoadjuvant therapy in comparison to non-responders [84].
The majority of OCT2 polymorphism studies have primarily focused
on the effect on cisplatin nephrotoxicity. There is one study in
lung cancer that evaluated the OCT2 polymorphisms. The poly-
morphisms rs195854 and rs186941 were associated with increased
response to cisplatin [85].
3.2. Increased cellular export of cisplatin
The export of cisplatin has been suggested to occur via passive
efflux, however the issue with studies to examine this phenom-
32 L. Amable / Pharmacological Research 106 (2016) 27–36
ena are performed with high concentration of cisplatin. Thus it is
thought that export of cisplatin from cells occurs via membrane
transporters. There are two major pathways in which cisplatin is
removed from the cell: removal by P-type ATPase transporters or
removal by ATP-binding cassette transporters.
3.2.1. P-type ATPase transporters
Cisplatin is exported by ATP7A and ATP7B, which belong to the
transporter family of P-type ATPases which use ATP to export. These
transporters are associated with removing excessive copper from
cells. Under normal conditions within the cell, ATP7A and ATP7B
are found in the trans-Golgi network and are trafficked to the cell
membrane to remove copper. As mentioned earlier, copper levels
are lower in cisplatin resistant cells which is additionally regulated
by ATP7A and ATP7B. Defects in these transporters are associated
with diseases with excessive copper accumulation: ATP7A is defec-
tive in Menkes disease while ATP7B is defective in Wilson’s disease
[86].
ATP7A is found is most tissues, aside from the liver. Increased
ATP7A expression is found in cancer cells but not in normal tis-
sue [87]. Increased expression of ATP7A in cells renders the cells
resistant to cisplatin but interestingly this was not due to altered
cisplatin export [88,89]. There are only a few clinical studies eval-
uating the role of ATP7A and cisplatin resistance. In NSCLC and
ovarian cancer, increased ATP7A expression is associated with a
poorer response to cisplatin [87,89]. ATP7A levels are addition-
ally higher in NSCLC tumors that are resistant to cisplatin [90].
No ATP7A polymorphisms have been identified with sensitivity
to cisplatin, though studies are very limited in examining ATP7A
polymorphisms in general [91].
ATP7B is found mostly in the liver, kidney and brain. Similar
observations found with ATP7A in terms of cisplatin resistance
have also been observed with ATP7B. ATP7B was first proposed
to be a biomarker of cisplatin resistance, as transfection of ATP7B
into cells resulted in an increase in cisplatin resistance accompa-
nied by reduced cisplatin accumulation [92]. Increased expression
of ATP7B is associated with poorly differentiated tumors and are
poor responders to cisplatin therapy in a variety of cancers includ-
ing: gastric, hepatocellular, esophageal, oral, breast, endometrial,
lung, and ovarian [93–101]. Currently, there are no identified ATP7B
polymorphisms that are associated with cisplatin resistance.
3.2.2. ATP-binding cassette (ABC) transporters
Multidrug resistance-associated proteins (MRPs), belong to the
ABCC subfamily of ABC (ATP-binding cassette) transporters and
been implicated in cisplatin resistance [102]. MRPs are membrane
transporters responsible for the efflux of glutathione-platinum
conjugates, in an ATP-dependent fashion. MRP1 was first explored
as a cisplatin transporter as it was found that cisplatin resis-
tant cells displaying increased levels of glutathione concurrently
had increased levels of MRP1 [103]. Reports from other groups
suggested that MRP1 alone was not enough to confer cisplatin resis-
tance and there is no relationship between MRP1 and cisplatin
accumulation and cytotoxicity [104–106]. There are no polymor-
phisms of MRP1 associated with cisplatin response as well. Thus,
MRP1 is generally not thought to play a role in cisplatin resistance.
MRP2, also known as cMOAT (canalicular multispecific organic
anion transporter), is the most favored MRP transporter contribut-
ing to cisplatin resistance. Overexpression of MRP2 is found in a
variety of cisplatin resistant cells lines [107–109]. The expression
of MRP2 is induced by cisplatin as well [110]. In the clinic, there
are different observations in correlating MRP2 expression with
cisplatin sensitivity, which may reflect the tissue specific nature
of the transporter. Increased MRP2 expression is associated with
cisplatin resistance in colorectal, esophageal, and hepatocellular
cancers [111–113]. However, in ovarian and lung cancer MRP2 did
not predict cisplatin response [100,114,115]. One polymorphism
in MRP2, C-24T, has been correlated with increased response to
platinum-based chemotherapy in lung cancer [116,117]. The C-24T
polymorphism is found in the promoter of MRP2 and its function
is not currently known.
4. Cytosolic inactivation of cisplatin
Finally, the last resistance mechanism is cytosolic inactivation
of cisplatin. This inactivation results in the inability of cisplatin
to react with DNA. Less damage is produced and the cancer cell
survives the drug treatment. The primary form of inactivation is
conjugation of cisplatin with glutathione (GSH), resulting in cellu-
lar export by the MRP transporters, discussed in the prior section.
The secondary form of inactivation is by binding to metallothionein
proteins.
4.1. Inactivation by glutathione conjugation
Glutathione-S-transferases (GSTs) catalyze the conjuga-
tion of glutathione (GSH) to cisplatin. The formation of
platinum–glutathione conjugates inactivates the drug by increas-
ing its solubility, leading to excretion. Inside the cell, glutathione
acts as antioxidant. It maintains the redox environment by keeping
reduced sulfhydryl groups [118]. Depletion of cellular GSH in
cisplatin resistant cells enhances the cytotoxicity of cisplatin [119].
However, the cisplatin sensitivity is not restored to levels of the
parental cell lines. In ovarian cancer cells, increased levels of GSH
were observed in platinum resistant cell lines [120]. There are two
families of GST enzymes involved in cisplatin detoxification-GSTP1
and GSTM.
4.1.1. Glutathione-S-transferase Pi 1
GSTP1, also called GST Pi 1, is expressed in different epithelial
tissues. The cellular and clinical studies of GSTP1 are inconclu-
sive as to whether or not it is an indicator of cisplatin resistance.
In colon, lung, and glioblastoma cancer cell lines, the levels of
GSTP1 are correlated with high GSTP1 expression and increased
cisplatin resistance [121]. In ovarian and head and neck carcinoma
patient samples, there is a correlation between high expression of
GSTP1 and cisplatin resistance [122–124]. Several studies in NSCLC
have demonstrated that low levels of GSTP1 are associated with
increased sensitivity to cisplatin [125–129]. However, in other clin-
ical studies of ovarian and cervical cancer there was no association
of GSTP1 levels and response to cisplatin chemotherapy [130–132].
GSTP1 has two polymorphisms: rs1695 and rs1138272. Similar
to the expression data, GSTP1 polymorphism data is conflicting and
inconclusive. The rs1695 polymorphism affects the ability of GSTP1
to conjugate GSH to cisplatin [133]. Studies in NSLC have yielded
multiple results for the GSTP1 rs1695 polymorphism: associated
with a favorable response to cisplatin therapy [116,134], associated
with reduced survival to cisplatin therapy [135], and no association
with survival [136]. The rs1138272 polymorphism additionally has
different responses to cisplatin therapy: one study found it was
associated with greater median survival [136] and another study
correlated to the polymorphisms to a shorter event free survival
and shorter overall survival in osteosarcoma patients [61].
4.1.2. Glutathione-S-transferase Mu
GSTM, or GST Mu, is the other GST involved in the inactiva-
tion of cisplatin. GSTM is more known for the detoxification of
xenobiotics thus there is little research in evaluating GSTM in cis-
platin resistance. There are five GSTM genes: GSTM1–GST5. Earlier
studies showed that there was no difference and no contribution
by GSTMs to cisplatin resistance [137–139]. However, recent data
using a paired cisplatin sensitive/resistant breast cancer cell line
 L. Amable / Pharmacological Research 106 (2016) 27–36
demonstrated decreased GSTM3 and GSTM4 levels were found
in cisplatin resistant cells compared to sensitive cells [140,141].
This has not been investigated further as one would assume that
decreased levels of GSTs would show decreased resistance to
cisplatin, like observed with GSTP1. However, pharmacologic inhi-
bition of GSTM1 resulted in the increased sensitivity of cells to
cisplatin [142]. There are no clinical studies examining the rela-
tionship of GSTM levels with cisplatin sensitivity.
The majority of GSTM polymorphism studies have focused on
the susceptibility to cancer and not so much on the relationship
with cisplatin resistance. GSTM2 and GSTM5 do not have any
reported polymorphisms. Polymorphisms for GSTM3 and GSTM4
have not been evaluated for their relationship with cisplatin resis-
tance. There are few studies with polymorphisms of GSTM1.
Wheeler et al. showed that the rs10431718 GSTM1 polymorphism
was associated with the cisplatin IC50 [143]. In a NSCLC meta-
analysis, the GSTM1 null genotype was associated with improved
response to platinum therapy [144].
4.2. Inactivation by metallothionein binding
Finally, cisplatin is also inactivated by binding to metalloth-
ionein (MT) proteins. MT proteins are cysteine-rich, low molecular
weight proteins that bind to metals such as copper, zinc, cadmium,
and mercury. While there are multiple MTs, mostly MTI and MTII
have studied since they are ubiquitously expressed. However, it is
not always evident which MT is being examined. MTs function as
regulators of cellular metal homeostasis as well as detoxification of
heavy metal exposure in cells. In terms of cisplatin resistance, MTs
serve as a heavy-metal detoxifier of cisplatin in tumors. Overex-
pression of metallothionein has been observed in several cell lines
that are resistant to cisplatin [145–147]. Additionally, the overex-
pression of MTII confers resistance to cisplatin in cancer cells [148].
Cisplatin treatment induces the expression of MT [149]. In germ
cell tumors, MT expression was higher in cell lines and tumors,
but there was no difference between patients who responded
to cisplatin based therapy compared to non-responders [150]. In
esophageal cancer, expression of MT was associated with a shorter
survival rate after cisplatin therapy [151]. This was additionally
observed in ovarian cancer patients receiving cisplatin based ther-
apy [123]. There are no MT polymorphisms that are associated with
cisplatin resistance.
5. Summary
Cisplatin is a clinical mainstay for the treatment of a vari-
ety of cancers. Unfortunately, many tumors develop resistance
and are refractory to treatment. Resistance stems from three
overall mechanisms-increased DNA repair, altered drug cellular
accumulation, and increased drug cytosolic inactivation. In this
review, potential biomarkers and their known polymorphisms for
each resistance mechanism were examined and are summarized
in Tables 1 and 2. While ERCC1 represents the most promising
biomarker for cisplatin resistance, as it has been extensively studied
in a variety of cancers, there are several opportunities and areas ripe
for further study. Other components of NER, CTR1 and CTR2, OCT2,
ATP7A and ATP7B, GSTs, and metallothioneins have the potential
to be valid cisplatin biomarkers as well, and would benefit from
additional clinical studies.
While this list is comprehensive, there are several things to con-
sider. Not all biomarkers were examined in a multitude of cancer
types, so some may be tumor specific. Many biomarkers displayed
conflicting evidence with their role in cisplatin resistance. Some
of the conflicting data reflects the fact that many studies maybe
underpowered for the analyses, and would benefit from having
33
larger sample sizes. Because resistance to cisplatin is multilayered
and multifactorial, different mechanisms are likely to be activated
depending on the cancer type and stage. It is highly likely that
multiple resistance mechanisms will be activated within a patient.
While one biomarker may not be completely informative for all can-
cers, a combination of biomarker expression and polymorphism
screening may yield a comprehensive approach to elucidate the
resistance status of a patient.
The method by which patients are screened is critical. The
type of biospecimen used in the evaluation (blood, tissue, etc.),
the expression type (DNA, mRNA, protein), and the method used
to examine expression (PCR-based, IHC, etc.) will all need to be
standardized for analysis of resistance. The definition of what is
considered high versus low expression, as well as the cutoff points
between the categories, will also require standardization. A recent
paper described the challenge of biomarker based screening. In
a round robin analysis of three independent commercial labs, 18
tumor blocks were sent for testing of ERCC1 status, and the results
were inconsistent and unreliable [152]. Only 4 of 18 blocks tested
were fully concordant with ERCC1 status between all three labs.
Thus further evaluation and standardization are needed before
these assays become clinical standard-of-care.
Precision medicine serves two purposes for cisplatin resistance:
to determine if resistance is occurring and to determine the nature
of the activated resistance mechanism(s). Screening the patient
prior to initiation of treatment, and during the course of treat-
ment, allows for the improvement of cancer diagnosis by predicting
tumor response. Personalizing this therapy will increase the effi-
cacy and decrease the toxicity of platinum-based chemotherapy.
While there is a long road ahead, several of the biomarkers listed
here may serve as a foundation for larger, prospective studies to
determine which biomarker, or combination of biomarkers, would
result in the best prediction of cisplatin sensitivity and resistance
in patients.
Conflict of interest
The author has no conflict of interest.
Acknowledgments
The research was supported by the Intramural Research Pro-
gram of the NIH, National Institute on Minority Health and Health
Disparities. This manuscript is dedicated to my former mentor, Dr.
Eddie Reed.
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