1.

1 LUNG CANCER

1.1.1 Statistics and risk factors

Worldwide, cancer is the second leading cause of death after cardiovascular

diseases, with lung cancer being the leading cause of cancer-related deaths in men and

second-leading cause in women. In 2018, it was estimated that 1 in 5 cancer-related

deaths worldwide were due to lung cancer (ref 1).

In United States, lung cancer remains the most lethal cancer in both men and

women with 234,030 estimated new cases and 154,050 estimated deaths in 2018 alone.

At advanced stage of the disease, 5-year survival rate for lung cancer (4.2%) is lower

than other leading cancers, such as breast cancer (26.5%), prostate cancer (30%),

colorectal cancer (12.6%) and melanoma of skin (16%). Even at early onset of the

disease, stage I, the survival rates for lung and bronchus cancer is only 55.1% while for

other cancers its higher, such as, for breast cancer its 100%, for colorectal cancer its

88.1%, for melanoma of skin its 99.5% and for prostate cancer as well its >99%. The

dismal survival rates for lung cancer are chiefly because for more than half of the cases,

at the time of diagnosis, the disease is already at an advanced stage [ref 2&3].

Cigarette smoking remains the highest risk factor for lung cancer, amounting to

about 75% deaths in men and 50% in women, worldwide. Other risk factors include,

secondhand exposure to smoke, air pollution, environmental exposure to asbestos,

certain metals such as arsenic, organic chemicals, diesel exhaust and radon gas from

building materials. Some occupational exposures include, roofing, painting, chimney

sweeping and rubber manufacturing. History of pulmonary tuberculosis, as well as a

strong family history of lung cancer can also increase the risk of developing lung cancer

[ref 1].

1.1.2. Types of Lung Cancer

Depending on the cells in which the disease originates, lung cancer is of

two types. About 15% of lung cancers are categorized as Small-Cell Lung Cancer and

85% as Non-Small Cell Lung Cancer (NSCLC). NSCLC is further categorized into three

major subtypes: adenocarcinoma (~40%) and squamous cell carcinoma (~30%) and

large cell carcinoma (~15%).

1.1.3 Driver gene mutations and targeted treatments

In lung adenocarcinoma, most common mutations found are in TP53 (46%),

KRAS (33%), Epidermal Growth Factor Receptor (EGFR) tyrosine kinase (14%) and

BRAF (10%). Several tumor suppressor genes are also commonly mutated in

adenocarcinoma, such as STK11/LKB1 (17%), NF1 (11%), RB1 (4%), KEAP1 (17%)

and CDKN2A (4%). Other additional mutations found in adenocarcinoma are PIK3CA

mutation, MET splice mutation, mutation in GTPase gene RIT1, translocations in ALK,

ROS1 and RET, mutations in chromatin modifying genes, SETD2, ARIDA and

SMARCA4, mutations in RNA splicing genes, RBM10 and U2AF1. MGA gene that

encodes a MAX dimerizing protein for MAX in MYC-MAX complex is also found to be

commonly mutated [ref 5].

In lung squamous cell carcinoma, some significantly mutated genes include, TP53

(81%), CDKN2A (15%), PTEN (8%), PIK3CA (16%), KEAP1 (12%), MLL2 (20%), HLA-

A (3%), NFE2L2 (15%), NOTCH1 (8%) and RB1 (7%) [ref 6].

Treatment options targeted towards these driver mutations is the approach

increasingly being adopted for personalized therapy, as opposed to cytotoxic traditional

chemotherapy. For example, in patients with EGFR-activating mutations, EGFR

tyrosine kinase inhibitors, gefitinib, erlotinib and afatinib are used primarily as first-line

of treatment. MEK inhibitor, selumetinib has been reported to improve survival in KRAS

mutation positive NSCLC patients. Crizotinib, a tyrosine kinase inhibitor is being used

for treatment of ALK as well as ROS1-translocation positive lung cancer patients. EGFR
monoclonal antibody necitumumab has been approved by Food and Drug

Administration (FDA) for treatment of patients with advanced squamous cell carcinoma.

Typically, T-cells recognize tumor cells as foreign as body’s immune response to the

disease. However, tumor cells can sometimes escape this immune response.

Monoclonal antibodies targeting immune-checkpoint modulating proteins, cytotoxic T-

lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), and

programmed death ligand 1 (PD-L1) have led to promising outcomes in patients with

many malignancies, including NSCLC [ref 7].

Despite such advances in treatment options, NSCLC demonstrates poor

patient prognosis and is often diagnosed at advanced stage. Hence, it clearly remains

an area of unmet medical need, where more in-depth knowledge of molecular origins of

the disease is required.

1.1.4 Cancer metastasis and EMT

Epithelial to mesenchymal transition (EMT) is an evolutionarily conserved process

essential in the process of gastrulation, embryonic development, wound healing,

organ fibrosis and cancer progression [book ref]. EMT is a process of reversible

reprogramming of cobblestone-shaped epithelial cells to more invasive and motile,

spindle-shaped mesenchymal cells [book ref]. The process of EMT has been widely

recognized for its role in cancer metastasis, rendering tumor cells a more invasive

phenotype, resistance to apoptosis, chemo-resistance and self-renewing cancer stem

cell like properties [book ref]. Following EMT, cells disseminate to distant organs

where owing to the plasticity of this process, cells undergo EMT reversion, that is
Mesenchymal-to-Epithelial Transtition (MET) which is essential for colonization and

secondary tumor formation at these distant sites [book ref].