Cancer: Tumours addicted to drugs are

vulnerable
• Rebecca J. Lee
• & Richard Marais

Cancer cells can develop an 'addiction' to the drugs they are

treated with, so that they need the drugs to survive. Analysis
of the underlying mechanism reveals a potential clinical
strategy for harnessing this phenomenon. See Letter p.270

As cancer cells become resistant to drugs that target cancer-

specific signalling pathways, an intriguing phenomenon called
drug addiction sometimes develops1. This occurs when cells that
are resistant to drug treatment become dependent on the drug.
On page 270, Kong et al.2provide insights into the mechanisms
underlying drug addiction in cancer. Their findings have major
implications for the use of targeted tumour therapies.

The authors studied cultured cell samples of a type of human skin

cancer called melanoma. They treated the cells with the drug
dabrafenib, which is used to target the BRAF protein in cancers
that have a cancer-causing mutation in the BRAF gene.
Alternatively, the authors treated the cells with both dabrafenib
and the drug trametinib, which targets an enzyme in the BRAF
pathway called MEK. They identified drug-addicted cells, which
died if they did not receive drug treatment.

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 ‫ُ‬
‫اﻟﻌﻘﺎﻗ� �ﻀﻌﻔﻬﺎ‬
‫ي‬ ‫�ﻃﺎن‪ :‬إدﻣﺎن اﻷورام ﻋ�‬
‫ر�ب�كﺎ ﺟ�ﻪ‪ .‬ي�‪ ،‬ور�تﺸﺎرد ﻣﺎر�ﻪ‬

‫�‬ ‫� ُ �‬ ‫ّ‬
‫بﺤﺎﺟﺔ إﻟﻴﻬﺎ‪ ،‬ي�‬
‫ٍ‬ ‫ﺗﺼ�‬
‫اﻟى ﺗﻌﺎﻟﺞ ﺑﻬﺎ‪ ،‬ﺣى إﻧﻬﺎ ي‬
‫ي‬ ‫اﻷدو�ﺔ‬ ‫ﻦ"‬ ‫"ﺗﺪﻣ‬
‫ِ‬ ‫ﻗﺪ‬ ‫اﻟ�ﻃﺎﻧ�ﺔ‬ ‫اﻟﺨﻼ�ﺎ‬ ‫إن‬
‫ّ‬ ‫�‬ ‫�ﺴﺘﻤﺮ ن� اﻟبﻘﺎء‪� .‬ﻜﺸﻒ ﺗﺤﻠ�ﻞ ّ‬
‫اﻵﻟ�ﺔ اﻟ�ﺎﻣﻨﺔ وراء هﺬە اﻟﻈﺎهﺮة ﻋﻦ اﺳ�اﺗ�ﺠ�ﺔ إ�ﻠﻴن�ﻜ�ﺔ‬ ‫ِ‬ ‫َ ي‬
‫ﻣﺤﺘﻤﻠﺔ ﻻﺳﺘﻐﻼﻟﻬﺎ‪.‬‬
‫اﻟي �ﺴﺘﻬﺪف ﻣﺴﺎرات ﺗﺄﺷ� ّ‬ ‫ﻟﻠﻌﻘﺎﻗ� �‬ ‫َ ن‬
‫ﺧﺎﺻﺔ بﺎﻟ�ﻃﺎن‪،‬‬ ‫ي‬ ‫ي‬ ‫ي‬ ‫اﻟ�ﻃﺎن‬ ‫ﺧﻼ�ﺎ‬ ‫�‬‫ي‬ ‫ﻣﻊ �ﺸﻮء ﻣﻘﺎوﻣﺔ‬
‫اﻟﻌﻘﺎﻗ�‪َ ،1‬ﺗ ْﺤ ُﺪث ي ن‬ ‫أﺣ�ﺎﻧﺎ ﻇﺎهﺮة ﻣﺜ�ة ﻟﻼهﺘﻤﺎم‪ُ ،‬‬ ‫ً‬ ‫ُ‬
‫ﺣن ﺗﺼﺒﺢ اﻟﺨﻼ�ﺎ‬ ‫ي‬ ‫إدﻣﺎن‬ ‫ﻋﻠﻴﻬﺎ‬ ‫ﻄﻠﻖ‬‫�‬ ‫ي‬ ‫ﺗﻈﻬﺮ‬
‫َﱠ‬ ‫ً ن‬ ‫ن ْ ُ‬ ‫ُ‬
‫ﻣﺆﺧﺮا ي� دور�ﺔ‪ ،Nature‬ﻗﺪم ﻛﻮﻧﺞ‬ ‫بﺤﺚ � ��‬ ‫ﻣﻌﺘﻤﺪة ﻋﻠ�ﻪ‪ .‬ي‬
‫و�‬ ‫ِ‬ ‫ﻘﺎوﻣﺔ ﻟﻠﻌﻼج بﺎﻟﻌﻘﺎر‬ ‫اﻟﻤ �‬
‫وﺗﺤﻤﻞ اﻟﻨﺘﺎﺋﺞ‬
‫ِ‬ ‫اﻟﻌﻘﺎﻗ� ن ي� اﻟ�ﻃﺎن‪.‬‬
‫ي‬ ‫ﻟﻶﻟ�ﺎت اﻟ�ﺎﻣﻨﺔ وراء ﻇﺎهﺮة إدﻣﺎن‬ ‫وزﻣﻼؤە ‪2‬رؤى ﻣﺘﻌﻤﻘﺔ ّ‬
‫ﱠ‬
‫اﻟﻤﻮﺟﻬﺔ‪.‬‬ ‫ﻃ�ﺎﺗﻬﺎ ﺗبﻌﺎت ﻣﻬﻤﺔ ﻋ� اﺳﺘﺨﺪام ﻋﻼﺟﺎت اﻷورام‬ ‫اﻟى ﺗﻮﺻﻠﻮا إﻟﻴﻬﺎ �� ّ‬ ‫�‬
‫ي‬ ‫ي‬

‫ﺴ� اﻟﻮرم‬‫اﻟب�‪ �ُ ،‬ﱠ‬‫ﻋﻴﻨﺎت ﺧﻠ��ﺔ ﻣﺰروﻋﺔ ﻟﻨ�ع ﻣﻦ �ﻃﺎن اﻟﺠﻠﺪ �ﺼ�ﺐ �‬ ‫ﻗﺎم اﻟبﺎﺣﺜﻮن بﺪراﺳﺔ ّ‬
‫اﻟ� ي ن‬ ‫ُ‬ ‫ن‬
‫وﺗن ‪BRAF‬‬ ‫اﻟﻤ�ﻼﻧﻴي‪ .‬وﻗﺪ ﻋﺎﻟﺠﻮا اﻟﺨﻼ�ﺎ بﻌﻘﺎر "داﺑﺮاﻓﻴن�ﺐ" اﻟﺬي �ﺴﺘﺨﺪم ﻻﺳﺘﻬﺪاف �‬
‫ي‬
‫اﻟﺠن ‪ ،BRAF‬ﺛﻢ ﻗﺎﻣﻮا بﻌﻼج اﻟﺨﻼ�ﺎ‪،‬‬ ‫ﻣﺴببﺔ ﻟﻠ�ﻃﺎن ن� ي ن‬
‫اﻟي ﺗﺤﻤﻞ ﻃﻔﺮة ﱢ‬ ‫�‬ ‫ن‬
‫ي‬ ‫ي� اﻟ�ﻃﺎﻧﺎت ي‬
‫ً ن‬ ‫بﺎﻟﺘﻨﺎوب‪ّ ،‬‬
‫إﻧ��ﻤﺎ ي� ﻣﺴﺎر‬ ‫بكﻞ ﻣﻦ اﻟﻌﻘﺎر�ﻦ "داﺑﺮاﻓﻴن�ﺐ"‪ ،‬و"ﺗﺮاﻣﻴتﻴن�ﺐ" اﻟﺬي �ﺴﺘﻬﺪف‬
‫ّ‬ ‫�‬
‫وﺗﻤﻜﻨﻮا ﻣﻦ ﺗﺤﺪ�ﺪ اﻟﺨﻼ�ﺎ اﻟﻤﺪﻣﻨﺔ‪� ،‬‬
‫اﻟي ﺗﻤﻮت‪ ،‬إذا ﻟﻢ ﺗﺘﻠﻖ اﻟﻌﻘﺎر‪.‬‬
‫ي‬ ‫‪َ �ُ BRAF‬ﺴ ّ� ‪MEK.‬‬

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To find the mechanism responsible for drug addiction in this
context, Kong and colleagues used a genetic-engineering
technique to delete genes in the cells. They withdrew dabrafenib
from the engineered cells, then analysed the surviving cells for
genes whose deletion prevented the cell death or growth arrest
that usually occurs in drug-addicted cells when the drug is
withdrawn. These experiments enabled the authors to identify two
genes that they verified were involved in the drug-addiction
process. The genes encode the proteins ERK2 and JUNB, which
have roles in the BRAF-mediated signalling pathway. Then, using
a panel of drug-resistant cell lines and in vitro and in
vivo experiments, Kong et al. demonstrated that genetic depletion
of MAPK1 (which encodes ERK2), JUNB or FOSL (which encodes
JUNB's binding partner protein, FRA1) blocked the death of drug-
addicted cells.

The authors uncovered an exquisite specificity of action of the

proteins involved. For example, depletion of ERK2 prevented cell
death associated with drug addiction, but depletion of ERK1 had
no effect on this process. This is consistent with the observation
that when the drug was withdrawn from drug-addicted cells, ERK2
but not ERK1 was hyperactivated, even though both act in the
same signalling pathway.

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 ‫ن‬ ‫وﻣﻦ أﺟﻞ ا�تﺸﺎف ّ‬
‫ﻟﻠﻌﻘﺎﻗ� ي� هﺬا اﻟﺴ�ﺎق‪ ،‬اﺳﺘﺨﺪم ﻛﻮﻧﺞ‬ ‫ي‬ ‫اﻵﻟ�ﺔ اﻟﻤﺴﺆوﻟﺔ ﻋﻦ إدﻣﺎن اﻟﺨﻼ�ﺎ‬
‫�ﺴ ْﺤﺐ اﻟﻌﻘﺎر‬ ‫ﺗﻘﻨ�ﺔ ن� اﻟﻬﻨﺪﺳﺔ اﻟﻮراﺛ�ﺔ ﻟﺤﺬف ﺟﻴﻨﺎت ﻣﻦ اﻟﺨﻼ�ﺎ‪ ،‬ﺣ�ﺚ ﻗﺎﻣﻮا َ‬ ‫وزﻣﻼؤە ّ‬
‫ُ ﱠ‬ ‫ي‬
‫اﻟي ﻣﻨﻊ‬ ‫اﺛ�ﺎ‪ ،‬ﺛﻢ بﺤﺜﻮا ن� اﻟﺨﻼ�ﺎ اﻟﻨﺎﺟ�ﺔ ﻋﻦ اﻟﺠﻴﻨﺎت �‬ ‫ﻌﺪﻟﺔ ور �‬ ‫"داﺑﺮاﻓﻴن�ﺐ" ﻣﻦ اﻟﺨﻼ�ﺎ اﻟﻤ‬
‫ي‬ ‫ي ن‬ ‫َ ْ ُ‬ ‫ّ‬ ‫ّ‬
‫ﻟﻠﻌﻘﺎﻗ� ﻋﻨﺪﻣﺎ ﻳﺘﻢ‬
‫ي‬ ‫اﻟﻤﺪﻣﻨﺔ‬ ‫اﻟﺨﻼ�ﺎ‬ ‫�‬
‫ي‬ ‫ﻋﺎدة‬ ‫ث‬ ‫ﺪ‬ ‫ﺤ‬ ‫�‬ ‫ﻣﺎ‬ ‫هﺎ‪،‬‬ ‫ﻧﻤﻮ‬ ‫ﻒ‬ ‫ﺗﻮﻗ‬ ‫ﺣﺬﻓﻬﺎ ﻣﻮت اﻟﺨﻠ�ﺔ‪ ،‬أو‬
‫ﺟﻴﻨن ي ن‬
‫ين‬ ‫ﱡ‬ ‫ين‬ ‫�‬
‫اﺛﻨن‪ ،‬أﺛبﺘﻮا‬ ‫اﻟﺘﻌﺮف ﻋ�‬ ‫اﻟبﺎﺣﺜن ﻣﻦ‬ ‫ﺳﺤﺐ اﻟﻌﻘﺎر‪ .‬وﻗﺪ ﻣﻜﻨﺖ هﺬە اﻟﺘﺠﺎرب‬
‫َ‬ ‫َ‬
‫وﺗيﻨ ي ن‬ ‫ﱢ‬ ‫ّ‬ ‫ن‬
‫ن ‪ ،ERK2‬و‪ ،JUNB‬اﻟﻠﺬﺑﻦ‬ ‫اﻟ�‬‫�‬ ‫اﻟﺠﻴﻨﺎن‬ ‫ﺮ‬ ‫�ﺸﻔ‬ ‫ﻟﻠﻌﻘﺎﻗ�‪.‬‬
‫ي‬ ‫ﻋﻤﻠ�ﺔ إدﻣﺎن اﻟﺨﻼ�ﺎ‬ ‫إﺳﻬﺎﻣﻬﻤﺎ ي�‬
‫ين‬ ‫ن‬
‫ﺑﺮوﺗن ‪ .BRAF‬و�ﺎﺳﺘﺨﺪام ﻣﺠﻤﻮﻋﺔ ﻣﻦ ﺧﻄﻮط‬ ‫اﻟﺘﺄﺷ� اﻟﺬي ﻳﺘﻮﺳﻄﻪ‬ ‫ي‬ ‫بﺪور ي� ﻣﺴﺎر‬ ‫�‬ ‫�ﻘﻮﻣﺎن‬
‫ن‬ ‫ن‬ ‫ُ‬
‫اﻟ�‪ ،‬ا�تﺸﻒ ﻛﻮﻧﺞ وزﻣﻼؤە أن‬ ‫و� اﻟﺠﺴﻢ ي‬ ‫اﻟﻤﺨﺘ�‪ ،‬ي‬ ‫�‬ ‫ﻟﻠﻌﻘﺎﻗ�‪ ،‬وﺗﺠﺎرب ي�‬ ‫ي‬ ‫ﻘﺎوﻣﺔ‬ ‫�‬ ‫ﺧﻠ��ﺔ ﻣ‬
‫ُ َ ﱢ‬ ‫ﱢ‬ ‫َ‬
‫ﺑﺮوﺗن ‪ ،(ERK2‬أو ‪ ،JUNB‬أو ‪) FOSL‬اﻟﺬي �ﺸﻔﺮ‬ ‫ين‬ ‫اﻟﺠن ‪) MAPK1‬اﻟﺬي ُ�ﺸﻔﺮ‬ ‫اﺳتﻨﻔﺎد ي ن‬
‫ُ ْ‬ ‫ن‬ ‫َ‬ ‫اﻟﻤﺸﺎرك ن� ر�ﻂ ‪ُ ،JUNB‬‬
‫اﻟﻤﺪ ِﻣﻨﺔ‬ ‫ﺴ� ‪ (FRA1‬ﻗﺪ � َﺴ ﱠبﺐ ي� ﻣﻨﻊ ﻣﻮت اﻟﺨﻼ�ﺎ‬ ‫و� ﱠ‬
‫ي‬ ‫�‬
‫وﺗن ُ‬ ‫اﻟ� ي ن‬
‫�‬
‫ﻟﻠﻌﻘﺎﻗ�‪.‬‬
‫ي‬

‫ن‬ ‫ن‬ ‫ّ‬ ‫َ‬

‫اﻟﻤﺸﺎرﻛﺔ ي� هﺬە اﻟﻈﺎهﺮة‪ .‬ﻓﻌ�‬
‫�‬ ‫اﻟ�وﺗيﻨﺎت‬ ‫ﺧﺼﻮﺻ�ﺔ ﻣﺬهﻠﺔ ي� ﻋﻤﻞ �‬ ‫ﻛﺸﻒ اﻟبﺎﺣﺜﻮن ﻋﻦ‬
‫اﻟﻌﻘﺎﻗ�‪ ،‬إﻻ أن‬
‫ي‬ ‫وﺗن ‪ ERK2‬ﻣﻮت اﻟﺨﻼ�ﺎ اﻟﻤﺮﺗبﻂ ﺑ�دﻣﺎن‬ ‫اﻟ� ي ن‬ ‫ﺳب�ﻞ اﻟﻤﺜﺎل‪ ،‬ﻣﻨﻊ اﺳتﻨﻔﺎد �‬
‫ّ‬ ‫ن‬ ‫اﻟ� ي ن‬
‫ﺗﺄﺛ� ي� هﺬە اﻟﻌﻤﻠ�ﺔ‪ .‬و�تﺴﻖ ذﻟﻚ ﻣﻊ اﻟﻤﻼﺣﻈﺔ بﺄﻧﻪ‬ ‫وﺗن ‪ ERK1‬ﻟﻢ �ﻜﻦ ﻟﻪ ي‬ ‫اﺳتﻨﻔﺎد �‬
‫�ﺸكﻞ‬ ‫وﺗن ‪ ERK2 -‬وﻟ�ﺲ ‪ERK1 -‬‬‫اﻟ� ي ن‬‫ﺣﻴﻨﻤﺎ ﺗﻢ ﺳﺤﺐ اﻟﻌﻘﺎر ﻣﻦ اﻟﺨﻼ�ﺎ اﻟﻤﺪﻣﻨﺔ‪� ،‬ﺸﻂ �‬
‫ٍ‬ ‫ن‬
‫اﻟﺘﺄﺷ� ذاﺗﻪ‪.‬‬
‫ي‬ ‫ﻣﻔﺮط‪ ،‬رﻏﻢ أن كﻠﻴﻬﻤﺎ �ﻌﻤﻼن ي� ﻣﺴﺎر‬

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The drug-addiction pathway was the same regardless of how drug
resistance had developed in a particular cell, for example by
increased activation of the ERK pathway, or by an increase in the
number of copies of BRAF. So the authors' findings might have
relevance for the treatment of many people who have drug-
resistant melanoma.

To determine how drug-addicted cells die when the drug is

withdrawn, the authors sequenced RNA in this type of dying cell.
As the cells died, the expression of genes associated with cell
proliferation decreased, whereas there was increased expression
of genes associated with metastasis — the ability of cells to
spread to new locations in the body. This finding links drug
addiction to phenotypic switching, an ability of melanoma cells to
switch between a proliferative state and an invasive cellular state
associated with metastasis.

Phenotypic switching underlies the plasticity of melanoma cells

and their ability to adapt to their microenvironment. The cellular
state of melanoma cells can be identified by monitoring the
expression of the E-cadherin protein or other proteins that are
characteristic of a change — known as the EMT — that occurs
when epithelial cells transition to become mesenchymal cells4.
Phenotypic switching results in a cellular state in which cells have
an increased probability of becoming metastatic, and the EMT
change is part of the process that enables cells to metastasize.
The EMT is regulated4 in melanoma by the transcription factor
protein MITF, which is the master regulator of the melanocyte-cell
lineage5 from which melanoma arises.

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 ‫ﻛ�ﻔ�ﺔ ﱡ‬
‫ّ‬ ‫ّ‬ ‫ً ن‬
‫ﺗﻄﻮر‬ ‫بﻐﺾ اﻟﻨﻈﺮ ﻋﻦ‬ ‫ﻟﻠﻌﻘﺎﻗ� ﻣﺘﻤﺎﺛﻼ ي� ﺟﻤﻴﻊ اﻟﺤﺎﻻت‪،‬‬
‫ي‬ ‫كﺎن ﻣﺴﺎر إدﻣﺎن اﻟﺨﻼ�ﺎ‬
‫ن‬ ‫ً‬ ‫اﻟﻤﻘﺎوﻣﺔ ن� ّ‬
‫َ‬
‫ﺧﻠ�ﺔ بﻌﻴﻨﻬﺎ‪ ،‬ﻋﻦ ﻃ��ﻖ ز�ﺎدة ﺗنﺸ�ﻂ ﻣﺴﺎر ‪ ، ERK‬ﻣﺜﻼ‪ ،‬أو ز�ﺎدة ي� ﻋﺪد �ﺴﺦ‬ ‫ي‬
‫ّ ن‬ ‫ﱠ‬ ‫�‬ ‫‪.‬‬ ‫ين‬
‫ﻛﺜ�‬
‫اﻟئ ﺗﻮﺻﻞ إﻟﻴﻬﺎ اﻟبﺎﺣﺜﻮن ﻗﺪ ﺗﻜﻮن ذات أهﻤ�ﺔ ي� ﻋﻼج ي‬ ‫اﻟﺠن ‪ BRAF‬ﻟﺬا‪ ،‬ﻓﺈن اﻟﻨﺘﺎﺋﺞ ُ ي‬
‫ﻟﻠﻌﻘﺎﻗ�‪.‬‬ ‫ﻘﺎوﻣﺔ‬ ‫ّ‬ ‫ين‬
‫ي‬ ‫اﻟﻤﺼﺎﺑن بﺄورام ﻣ�ﻼﻧيﻨ�ﺔ ﻣ �‬ ‫ﻣﻦ‬

‫ُ ْ‬
‫اﻟﻤﺪ ِﻣﻨﺔ ﻋﻨﺪ َﺳ ْﺤﺐ اﻟﻌﻘﺎر ﻣﻨﻬﺎ‪ ،‬ﻗﺎم اﻟبﺎﺣﺜﻮن ﺑﻮﺿﻊ �ﺴﻠﺴﻞ‬ ‫ﻛ�ﻔ�ﺔ ﻣﻮت اﻟﺨﻼ�ﺎ‬ ‫ّ‬ ‫وﻟﺘﺤﺪ�ﺪ‬
‫�ة؛ ووﺟﺪوا أﻧﻪ ن� أﺛﻨﺎء ﻣﻮت اﻟﺨﻼ�ﺎ‪َ ،‬ﻗﻞّ‬ ‫َ‬ ‫ْ‬ ‫ُ‬
‫اﻟ��ي ﻟﻬﺬا اﻟﻨ�ع ﻣﻦ اﻟﺨﻼ�ﺎ اﻟﻤﺤﺘ ِ ن َ‬
‫ي‬ ‫َ‬ ‫ي‬ ‫اﻟﺤﻤﺾ اﻟﻨﻮوي �‬
‫اﻟﺘﻌﺒ� ﻋﻦ اﻟﺠﻴﻨﺎت اﻟﻤﺮﺗبﻄﺔ‬
‫ي‬ ‫اﻟﺘﻌﺒ� ﻋﻦ اﻟﺠﻴﻨﺎت اﻟﻤﺮﺗبﻄﺔ ﺑﺘكﺎﺛﺮ اﻟﺨﻼ�ﺎ‪ ،‬ﺑيﻨﻤﺎ ﺗﺰ َا�ﺪ‬ ‫ي‬
‫ن‬
‫و� ﻗﺪرة اﻟﺨﻼ�ﺎ ﻋ� اﻻﻧتﺸﺎر إ� ﻣﻮاﻗﻊ ﺟﺪ�ﺪة ي� اﻟﺠﺴﻢ‪ .‬ﻳ��ﻂ هﺬا اﻻ�تﺸﺎف‬ ‫ي‬ ‫بﺎﻟﻨﻘ�ﻠﺔ‪،‬‬
‫ّ‬
‫اﻟﻤ�ﻼﻧيﻨ�ﺔ‪،‬‬ ‫وﺗﺤﻮل اﻟﻨﻤﻂ اﻟﻈﺎهﺮي‪ ،‬وهﻮ ﻗﺪرة ﻟﺪى ﺧﻼ�ﺎ اﻷورام‬ ‫ﱡ‬ ‫ﻟﻠﻌﻘﺎﻗ�‪،‬‬ ‫ﺑن إدﻣﺎن اﻟﺨﻼ�ﺎ‬ ‫ين‬
‫ي‬ ‫�‬
‫ﺧﻠ��ﺔ اﺟﺘ�ﺎﺣ�ﺔ ﻣﺮﺗبﻄﺔ بﺎﻟﻨﻘ�ﻠﺔ‪.‬‬ ‫ّ‬ ‫وﺣﺎﻟﺔ‬ ‫ﺔ‪،‬‬ ‫ّ‬
‫ﺗكﺎﺛ��‬ ‫ﺣﺎﻟﺔ‬ ‫ن‬
‫ﺑن‬ ‫ل‬ ‫ّ‬
‫اﻟﺘﺤﻮ‬ ‫ﻣﻦ‬ ‫ﻨﻬﺎ‬ ‫ﺗﻤﻜ‬
‫ٍ‬ ‫ٍ‬ ‫ي‬

‫ّ‬
‫اﻟﻤ�ﻼﻧيﻨ�ﺔ‪ ،‬وﻗﺪرﺗﻬﺎ ﻋ�‬ ‫ﺗﺤﻮل اﻟﻨﻤﻂ اﻟﻈﺎهﺮي هﺬا هﻮ اﻟﺴبﺐ اﻟ�ﺎﻣﻦ وراء ﻣﺮوﻧﺔ اﻟﺨﻼ�ﺎ‬ ‫إن ّ‬
‫ّ‬ ‫ّ‬ ‫ّ‬ ‫ﱠ‬ ‫ّ‬
‫اﻟﻤ�ﻼﻧيﻨ�ﺔ‪ ،‬ﻋﻦ‬ ‫اﻟﺨﻠ��ﺔ ﻟﺨﻼ�ﺎ اﻷورام‬ ‫اﻟﺘﻌﺮف ﻋ� اﻟﺤﺎﻟﺔ‬ ‫اﻟﺘﻜ�ﻒ ﻣﻊ ﺑيﺌﺘﻬﺎ اﻟﻤﺼﻐﺮة‪ .‬و�ﻤﻜﻦ‬
‫ﺗﻤ� ﺣﺪوث‬ ‫اﻟي يﱢ ن‬ ‫اﻟ�وﺗيﻨﺎت �‬ ‫ﻏ�ە ﻣﻦ �‬‫كﺎده��ﻦ"‪ ،‬أو ي‬
‫ي‬ ‫ﺑﺮوﺗن "إي‪-‬‬ ‫ين‬ ‫اﻟﺘﻌﺒ� ﻋﻦ‬
‫ي‬ ‫ﻃ��ﻖ ﻣﺮاﻗبﺔ‬
‫ي‬
‫ﱡ‬
‫ﺴ� اﺧﺘﺼﺎرا‪ ، EMT‬ﺗﺘﺤﻮل ﻓ�ﻪ اﻟﺨﻼ�ﺎ اﻟﻈﻬﺎر�ﺔ إ� ﻣﺘﻮﺳﻄ�ﺔ‪ .4‬ﻳتﺴبﺐ ﺗﺤﻮل‬ ‫ّ‬ ‫ً‬ ‫ﺗﻐ�‪ �ُ ،‬ﱠ‬
‫ﱡ‬
‫ي‬
‫ّ‬ ‫ﱡ‬ ‫ن‬ ‫�‬ ‫ّ‬ ‫ن‬
‫ﺣﺎﻟﺔ ﺧﻠ��ﺔ ﻳ�ا�ﺪ ﻓﻴﻬﺎ اﺣﺘﻤﺎل ﺗﺤﻮل اﻟﺨﻼ�ﺎ إ� ﺧﻼ�ﺎ ﻧﻘ�ﻠ�ﺔ‪،‬‬ ‫اﻟﻨﻤﻂ اﻟﻈﺎهﺮي ي� �ﺸﻮء‬
‫ﻋﻤﻠ�ﺔ ﺗﻐ�ّ‬‫ّ‬ ‫َُ �‬ ‫ٍ ّ � َُ �‬ ‫ﺗﻐ� ‪ً EMT‬‬ ‫و�ﻜﻮن ّ‬
‫ي‬ ‫اﻟي ﺗﻤ�ﻦ اﻟﺨﻼ�ﺎ ﻣﻦ اﻻﻧتﺸﺎر‪ .‬وﺗﻨﻈﻢ‬ ‫ي‬ ‫ﺔ‬ ‫اﻟﻌﻤﻠ�‬ ‫ﻣﻦ‬ ‫ا‬ ‫ﺟﺰء‬ ‫ي‬
‫�‬ ‫ن‬ ‫ّ‬ ‫ن‬
‫ﺑﺮوﺗن ﻋﺎﻣﻞ اﻟنﺴﺦ‪ ، MITF‬وهﻮ اﻟﻤﻨﻈﻢ‬ ‫ي‬ ‫‪EMT 4‬ﺗﻠﻚ ي� اﻷورام اﻟﻤ�ﻼﻧيﻨ�ﺔ‪ ،‬ﻋﻦ ﻃ��ﻖ‬
‫ّ‬
‫اﻟي ﺗنﺸﺄ ﻣﻨﻬﺎ اﻷورام اﻟﻤ�ﻼﻧيﻨ�ﺔ‪.‬‬ ‫ّ‬
‫اﻟﻤ�ﻼﻧيﻨ�ﺔ‪� 5‬‬ ‫اﻟﺨﻼ�ﺎ‬ ‫ﻼﻻت‬ ‫ﻟﺴ‬ ‫اﻟﺮﺋ�ﺲ ُ‬
‫ي‬

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Low levels of MITF are associated with an invasive metastatic
state, whereas high levels are associated with proliferation4. The
authors found that, in drug-addicted cells containing high levels of
MITF, the MITF levels collapse on drug removal and the cells
adopt an invasive form. When the authors used genetic
engineering to prevent a decrease in MITF levels when drug was
removed, the cell death associated with drug withdrawal was
reduced. However, the role of MITF in this cell-death process is
unclear, given that low levels of MITF expression are not known to
cause cell death4.

Kong and colleagues' work has clinical relevance in that, when the
drug treatment was stopped, they identified a window during
which treatment of melanoma cells grown in vitro with the
chemotherapeutic agent dacarbazine could boost cell death (Fig.
1). The authors propose that stopping the use of BRAF and MEK
inhibitors, and starting the use of dacarbazine, would be more
effective than merely halting all drug treatments in what are called
'drug-holiday' approaches aimed at promoting cell death by
harnessing drug addiction.

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 ‫ّ‬
‫ﻧﻘ�ﻠ�ﺔ اﺟﺘ�ﺎﺣ�ﺔ‪ ،‬ﺑيﻨﻤﺎ ﺗﺮﺗبﻂ‬ ‫بﺤﺎﻟﺔ‬ ‫وﺗن ‪MITF‬‬ ‫اﻟ� ي ن‬
‫ﺗﺮﺗبﻂ اﻟﻤﺴﺘ��ﺎت اﻟﻤﻨﺨﻔﻀﺔ ﻣﻦ �‬
‫ُ ْ‬ ‫ٍ‬
‫ن‬ ‫اﻟ� ي ن‬
‫وﺗن اﻟﻤﺮﺗﻔﻌﺔ ﺑﺘكﺎﺛﺮ اﻟﺨﻼ�ﺎ‪ .4‬ا�تﺸﻒ اﻟبﺎﺣﺜﻮن أﻧﻪ ي� اﻟﺨﻼ�ﺎ اﻟﻤﺪ ِﻣﻨﺔ‬ ‫ﻣﺴﺘ��ﺎت �‬
‫ّ‬ ‫ين‬ ‫ﻟﻠﻌﻘﺎﻗ�‪� ،‬‬
‫ﺑﺮوﺗن ‪ ،MITF‬ﺗﻨﺎﻗﺼﺖ �ﺸﺪة ﻣﺴﺘ��ﺎت هﺬا‬ ‫اﻟي ﺗﺤﻮي ﻣﺴﺘ��ﺎت ﻣﺮﺗﻔﻌﺔ ﻣﻦ‬ ‫ي‬ ‫ي‬
‫وﺗن ﻋﻨﺪ ﺳﺤﺐ اﻟﻌﻘﺎر‪ ،‬واﺗﺨﺬت اﻟﺨﻼ�ﺎ هﻴﺌﺔ اﺟﺘ�ﺎﺣ�ﺔ‪ .‬وﻋﻨﺪﻣﺎ اﺳﺘﺨﺪم اﻟبﺎﺣﺜﻮن‬ ‫ْ‬ ‫َ‬ ‫اﻟ� ي ن‬
‫َ‬ ‫�‬
‫ّ‬ ‫ْ‬ ‫َ‬ ‫ن‬
‫اﻟﻬﻨﺪﺳﺔ اﻟﻮراﺛ�ﺔ‪ ،‬ﻟﻤﻨﻊ ﺣﺪوث اﻧﺨﻔﺎض ي� ﻣﺴﺘ��ﺎت ‪ MITF‬ﻋﻨﺪ ﺳﺤﺐ اﻟﻌﻘﺎر؛ ﻗﻞ ﻣﻮت‬
‫ّ‬ ‫�‬ ‫اﻟ�وﺗ ي ن‬ ‫اﻟﺨﻼ�ﺎ اﻟﻤﺮﺗبﻂ َ ْ‬
‫ﻋﻤﻠ�ﺔ ﻣﻮت اﻟﺨﻼ�ﺎ هﺬە ﻣﺎ زال‬ ‫ن ‪ MITF‬ي�‬ ‫�ﺴﺤﺐ اﻟﻌﻘﺎر‪ ،‬إﻻ أن دور �‬
‫�ﺴبﺐ ﻣﻮت اﻟﺨﻼ�ﺎ‪.4‬‬ ‫ﻌﺮف ﻋﻦ اﻧﺨﻔﺎض ﻣﺴﺘ��ﺎت اﻟﺘﻌﺒ� ﻋﻨﻪ أﻧﻬﺎ ﱢ‬
‫ي‬ ‫ﻏ� واﺿﺢ‪ ،‬ﺣ�ﺚ ﻻ ُ� َ‬ ‫ي‬

‫ن‬
‫�ﺤﻤﻞ اﻟﻌﻤﻞ اﻟﺨﺎص بﻜﻮﻧﺞ وزﻣﻼﺋﻪ ي� ﻃ�ﺎﺗﻪ أهﻤ�ﺔ ﻃﺒ�ﺔ‪ ،‬إذ إﻧﻬﻢ ﻋﻨﺪ إ�ﻘﺎف ﻋﻼج اﻟﺨﻼ�ﺎ‬
‫ن‬ ‫َ‬
‫اﻟﻤﺨﺘ�‬
‫�‬ ‫ّ‬
‫اﻟﻤ�ﻼﻧيﻨ�ﺔ اﻟﻨﺎﻣ�ﺔ ي�‬ ‫بﺎﻟﻌﻘﺎﻗ�‪ ،‬ا�تﺸﻔﻮا ﺛﻐﺮة‪ ،‬ﺣ�ﺚ � َﺴ ﱠبﺐ ﻋﻼج ﺧﻼ�ﺎ اﻷورام‬ ‫ي‬
‫ين‬ ‫ن‬ ‫ئ‬
‫ﺗﺤﻔ� ﻣﻮت اﻟﺨﻼ�ﺎ )اﻟﺸكﻞ ‪ .(1‬و�ﺮى‬ ‫اﻟ��ﻤ�ﺎئ "دا�ﺎر�ﺎز�ﻦ" ي�‬
‫ي‬ ‫بﺎﺳﺘﺨﺪام ﻋﺎﻣﻞ اﻟﻌﻼج‬
‫ن‬ ‫اﻟبﺎﺣﺜﻮن أن إ�ﻘﺎف اﺳﺘﺨﺪام ﱢ‬
‫ﻣﺜبﻄﺎت‪ ، BRAF‬و‪ ،MEK‬واﻟبﺪء ي� اﺳﺘﺨﺪام "اﻟﺪا�ﺎر�ﺎز�ﻦ"‬
‫َ‬
‫اﻟﻤﻘﺎر�ﺎت اﻟﻤﻌﺮوﻓﺔ‬ ‫و�‬ ‫‪،‬‬‫بﺎﻟﻌﻘﺎﻗ�‬ ‫اﻟﻌﻼﺟﺎت‬ ‫ﺟﻤﻴﻊ‬ ‫إ�ﻘﺎف‬ ‫د‬‫ﻣﺠﺮ‬ ‫ﺳ�ﻜﻮن �‬
‫أ�� ﻓﻌﺎﻟ�ﺔ ﻣﻦ ّ‬
‫ي‬ ‫ي‬ ‫ُ ْ �‬
‫ﺗﺤﻔ� ﻣﻮت اﻟﺨﻼ�ﺎ‪ ،‬ﻋﻦ ﻃ��ﻖ اﺳﺘﻐﻼل إدﻣﺎﻧﻬﺎ ﻟﻠﻌﻘﺎر‪.‬‬ ‫ين‬ ‫بﺎﺳﻢ "ﻋﻄﻠﺔ اﻟﺪواء"‪ ،‬وﺗﻬﺪف إ�‬

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Figure 1: Drug addiction in cancer cells.

Kong et al.2 investigated how a type of human cancer called

melanoma responds to drug treatment using cells grown in vitro.
When the cells are treated with inhibitor molecules that target the
proteins BRAF or MEK, most die, although some might be
resistant to the treatment and survive. If the resistant cells are
treated with the inhibitor for a prolonged period, a phenomenon
known as drug addiction can occur, in which the cells become
dependent on the drug and some cells might rely on it for survival.

Kong and colleagues identified several proteins involved in the

drug-addiction pathway, including the protein ERK2. The authors
observed high levels of ERK2 activation when inhibitor treatment
was withdrawn from drug-addicted cells, causing some cell death.
Furthermore, cell death could be increased if treatment with the
chemotherapeutic agent dacarbazine was started at the same
time as inhibitor treatment ceased.

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 ‫ن‬
‫اﻟﻌﻘﺎﻗ� ي� اﻟﺨﻼ�ﺎ اﻟ�ﻃﺎﻧ�ﺔ‪.‬‬
‫ي‬ ‫اﻟﺸكﻞ ‪ | 1‬إدﻣﺎن‬

‫ﺴ� اﻷورام‬ ‫اﻟب�‪ �ُ ،‬ﱠ‬ ‫اﻟى ﺗﺼ�ﺐ �‬ ‫ﻗﺎم ﻛﻮﻧﺞ وزﻣﻼؤە‪ 2‬بﺪراﺳﺔ اﺳﺘﺠﺎبﺔ ﻧ�ع ﻣﻦ اﻟ�ﻃﺎﻧﺎت �‬
‫ن ُ‬ ‫ن‬ ‫ي‬ ‫�‬
‫وﺣن ﻋﻮﻟﺠﺖ‬ ‫ي‬ ‫‪.‬‬‫اﻟﻤﺨﺘ�‬
‫�‬ ‫�‬ ‫إﻧﻤﺎؤهﺎ‬ ‫ﺗﻢ‬ ‫ﺧﻼ�ﺎ‬ ‫بﺎﺳﺘﺨﺪام‬ ‫بﺎﻟﻌﻘﺎﻗ�‪ ،‬وذﻟﻚ‬
‫ي‬ ‫ّ‬
‫اﻟﻤ�ﻼﻧيﻨ�ﺔ ﻟﻠﻌﻼج‬
‫ي‬
‫ﺗن ‪ ،BRAF‬أو ‪ ،MEK‬ﻣﺎﺗﺖ ﻏﺎﻟﺒ�ﺔ اﻟﺨﻼ�ﺎ‪ ،‬إﻻ أن‬ ‫اﻟ�و ي ن‬
‫اﻟئ �ﺴﺘﻬﺪف �‬ ‫اﻟﻤﺜبﻂ �‬ ‫ﱢ‬ ‫اﻟﺨﻼ�ﺎ بﺠ��ﺌﺎت‬
‫�‬ ‫ْ‬ ‫َ‬ ‫ي‬ ‫َ‬ ‫بﻌﻀﻬﺎ ر�ﻤﺎ َ‬
‫بﺎﻟﻤﺜبﻂ ﻟﻔ�ة ﻃ��ﻠﺔ‪� ،‬ﻤﻜﻦ‬ ‫ﱢ‬ ‫ﻘﺎوﻣﺔ‬ ‫ﻗﺎوم اﻟﻌﻼج؛ وﻧﺠﺎ‪ ،‬ﻟ�ﻦ إن ﻋﻮﻟﺠﺖ اﻟﺨﻼ�ﺎ ُ‬
‫اﻟﻤ‬
‫�‬ ‫ُ‬ ‫َ ْ ُ‬
‫ﻣﻌﺘﻤﺪة ﻋ� اﻟﻌﻘﺎر‪،‬‬
‫ِ‬ ‫اﻟﺨﻼ�ﺎ‬ ‫ﻓﻴﻬﺎ‬ ‫ﺗﺼﺒﺢ‬ ‫"‪،‬‬‫اﻟﻌﻘﺎﻗ�‬
‫ي‬ ‫"إدﻣﺎن‬ ‫بﺎﺳﻢ‬ ‫ﻌﺮف‬ ‫ﺗ‬ ‫ﻇﺎهﺮة‬ ‫ث‬ ‫ﺪ‬ ‫ﺣﻴﻨﻬﺎ أن ﺗﺤ‬
‫ﻌﺘﻤﺪ ﻋﻠ�ﻪ بﻌﺾ اﻟﺨﻼ�ﺎ ﻟﻠبﻘﺎء‪.‬‬ ‫َ‬
‫وﻗﺪ � ِ‬

‫ن‬ ‫ََ �‬
‫اﻟﻌﻘﺎﻗ�‪ ،‬ﻣﻨﻬﺎ‬
‫ي‬ ‫إدﻣﺎن‬ ‫ﻣﺴﺎر‬ ‫�‬‫ي‬ ‫�ﺴﻬﻢ‬ ‫ﺑﺮوﺗيﻨﺎت‬ ‫ﻋﺪة‬ ‫ﻋ�‬ ‫اﻟﺘﻌﺮف‬ ‫ﻣﻦ‬ ‫وزﻣﻼؤە‬ ‫ﻛﻮﻧﺞ‬ ‫ﻦ‬ ‫�‬ ‫ﺗﻤ‬
‫وﺗن ‪ .ERK2‬وﻗﺪ ﻻﺣﻆ اﻟبﺎﺣﺜﻮن ﻣﺴﺘ��ﺎت ﻋﺎﻟ�ﺔ ﻣﻦ ﺗنﺸ�ﻂ ‪ ERK2‬ﻋﻨﺪ َﺳ ْﺤﺐ اﻟﻌﻼج‬ ‫اﻟ� ي ن‬ ‫�‬
‫ﱠ‬ ‫َ‬ ‫ُ ﱢَ‬
‫بﺎﻟﻤﺜبﻂ ﻣﻦ اﻟﺨﻼ�ﺎ اﻟﻤﺪﻣﻨﺔ؛ ﻣﺎ ﺳبﺐ ﻣﻮت بﻌﺾ اﻟﺨﻼ�ﺎ‪ .‬و�ﺿﺎﻓﺔ إ� ذﻟﻚ‪� ،‬ﻤﻜﻦ ز�ﺎدة ﻣﻮت‬
‫ن‬ ‫ئ‬
‫اﻟ��ﻤ�ﺎئ "دا�ﺎر�ﺎز�ﻦ" ي� اﻟﻮﻗﺖ ﻧﻔﺴﻪ ﻹ�ﻘﺎف اﻟﻌﻼج‬
‫ي‬ ‫� ي‬
‫اﻟﻌﻼ�‬ ‫اﻟﺨﻼ�ﺎ‪ ،‬إذا بﺪأ ﻋﻼﺟﻬﺎ بﺎﻟﻌﺎﻣﻞ‬
‫َُ‬
‫بﺎﻟﻤﺜ ﱢبﻂ‪.‬‬

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The timing of drug treatment would be crucial. MEK inhibitors, in
particular, have extremely long half-lives (up to 10 days) and,
given that low levels of inhibition of this pathway could prevent cell
death caused by drug addiction, correctly timed drug
administration would be essential to achieve optimal benefit.
There is clinical evidence6 that retreatment with the targeted
therapy can be effective after a drug holiday that was
implemented as a result of disease progression or toxicity. The
phenotypic switch from proliferative to invasive states might reset
the sensitivity of the cells to targeted therapies, although this
needs to be investigated.

The authors also tested another type of cancer called non-small

cell lung cancer. They found that drug withdrawal decreases cell
growth and induces an EMT cellular transition in a drug-resistant
sample of these cancer cells grown in vitro and treated with an
inhibitor of the EGFR protein (mutations in this protein are often
associated with lung cancer). Again, this drug-addiction
phenomenon was prevented by depletion of ERK2 but not of
ERK1. These data suggest that drug addiction is a general feature
associated with treatment by drugs that target proteins, such as
EGFR, in the MAPK pathway. It will be interesting to discover
whether drug addiction extends to therapies that target other
signalling pathways, and to identify the key pathway components
responsible.

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 ‫َ‬ ‫ً‬ ‫�ﱢ‬ ‫ن‬
‫ﻛﺒ�ة‪ .‬ﻓﺘﺤﺪ�ﺪا‪ُ ،‬ﻣﺜ ﱢبﻄﺎت ‪MEK‬‬ ‫ﺗﻠ� اﻟﻌﻼج بﺎﻟﻌﻘﺎر أهﻤ�ﺔ ي‬
‫ي‬ ‫ي� هﺬە اﻟﺤﺎﻟﺔ‪� ،‬ﻜﻮن ﻟﺘﻮﻗ�ﺖ‬
‫�‬ ‫ﻓ�ات ﻋﻤﺮ اﻟﻨﺼﻒ اﻟﺨﺎﺻﺔ ﺑﻬﺎ إ� �‬ ‫ﺗﻤﺘﺪ �‬
‫ﻓ�ات ﻃ��ﻠﺔ ﺟﺪا )ﺗﺼﻞ إ� ‪ 10‬أ�ﺎم(‪ ،‬وﺣ�ﺚ إن‬
‫اﻟﻤﺴﺘ��ﺎت اﻟﻤﻨﺨﻔﻀﺔ ﻣﻦ اﻟﺘثﺒ�ﻂ ﻟﻬﺬا اﻟﻤﺴﺎر ﻗﺪ ﺗﻤﻨﻊ ﻣﻮت اﻟﺨﻼ�ﺎ‪� ،‬ﺴبﺐ إدﻣﺎﻧﻬﺎ‬
‫ﻓﺈن إﻋﻄﺎء اﻟﺪواء ن� اﻟﺘﻮﻗ�ﺖ اﻟﺼﺤﻴﺢ ﺳ�ﻜﻮن ن� �‬ ‫ّ‬
‫ور�ﺎ؛ ﻟﺘﺤﻘﻴﻖ أﻋ� ﻓﺎﺋﺪة ﻣﻤﻜﻨﺔ‪.‬‬ ‫اﻟﻌﻘﺎﻗ�‪،‬‬
‫ُ ْ �‬ ‫ً‬ ‫ﱠ‬ ‫َ‬ ‫�‬ ‫ي‬ ‫ي �‬
‫وﺛﻤﺔ أدﻟﺔ إ�ﻠﻴن�ﻜ�ﺔ‪ 6‬ﻋ� أن ﻣﻌﺎودة ﻋﻼج اﻟﺨﻼ�ﺎ بﺎﻟﻌﻼج اﻟﻤﻮﺟﻪ ﻗﺪ �ﻜﻮن ﻓﻌﺎﻻ بﻌﺪ ﻋﻄﻠ ٍﺔ‬
‫ﺤﻮل اﻟﻨﻤﻂ اﻟﻈﺎهﺮي ﻣﻦ‬ ‫دواﺋ�ﺔ ُﻧ ﱢﻔﺬت‪ ،‬ﻧت�ﺠﺔ ﺗﻄﻮر اﻟﻤﺮض‪ ،‬أو ﺣﺪوث �ﺴﻤﻢ‪ .‬وﻗﺪ ُ�ﻌ�ﺪ َﺗ ﱡ‬ ‫ّ‬
‫اﻟﻤ َﻮ ﱠﺟﻬﺔ‪ ،‬إﻻ أن‬ ‫ّ‬
‫اﻟﺘكﺎﺛ��ﺔ إ� اﻟﺤﺎﻟﺔ اﻻﺟﺘ�ﺎﺣ�ﺔ ﺗنﺸ�ﻂ ﺣﺴﺎﺳ�ﺔ اﻟﺨﻼ�ﺎ ﻟﻠﻌﻼﺟﺎت ُ‬ ‫اﻟﺤﺎﻟﺔ‬
‫ذﻟﻚ �ﺤﺘﺎج إ� اﻟﺪراﺳﺔ واﻟبﺤﺚ‪.‬‬

‫ُ‬ ‫ً‬ ‫ً‬

‫اﻟﺼﻐ�ة‪ .‬وﻗﺪ‬‫ي‬ ‫ﻏ�‬ ‫اﻟ�ﻃﺎن‪َ � ،‬ﺴ ّ� �ﻃﺎن اﻟﺮﺋﺔ ذا اﻟﺨﻼ�ﺎ ي‬ ‫َُ�‬
‫اﺧﺘ� اﻟبﺎﺣﺜﻮن أ�ﻀﺎ ﻧﻮﻋﺎ آﺧﺮ ﻣﻦ‬ ‫�‬
‫ﱢ‬ ‫ن‬ ‫ﱡ‬ ‫ّ‬ ‫ْ‬ ‫َ‬
‫ﺗﻐ� ‪ EMT‬اﻟﺨﻠﻮي ي� ﻋﻴﻨﺔ‬ ‫وﺟﺪوا أن ﺳﺤﺐ اﻟﻌﻘﺎر ﻣﻦ اﻟﺨﻼ�ﺎ �ﻘﻠﻞ ﻧﻤﻮهﺎ‪ ،‬و�ﺤﻔﺰ ﺣﺪوث ي‬
‫�‬
‫وﻣﻌﺎﻟﺠﺘﻬﺎ ﱢ‬ ‫اﻟ�ﻃﺎﻧ�ﺔ ُﻣﻘﺎوﻣﺔ ﻟﻠﻌﻘﺎﻗ�‪ ،‬وﺗﻢ إﻧﻤﺎؤهﺎ ن� اﻟﻤﺨﺘ�‪ُ ،‬‬ ‫ّ‬
‫بﻤﺜبﻂ‬ ‫�‬ ‫ي‬ ‫ي‬ ‫�‬ ‫ﻣﻦ هﺬە اﻟﺨﻼ�ﺎ‬
‫ً‬ ‫اﻟ� ي ن‬ ‫ن‬ ‫�ﻟ� ي ن‬
‫وﺗن ﻋﺎدة ��ﻃﺎن اﻟﺮﺋﺔ(‪ .‬وﻣﺠﺪدا‪ ،‬ﺗﻢ ﺗﻔﺎدي‬ ‫وﺗن ‪) EGFR‬ﺗﺮﺗبﻂ اﻟﻄﻔﺮات ي� هﺬا �‬
‫و�ﺸ� هﺬە اﻟﺒ�ﺎﻧﺎت إ�‬ ‫ي‬ ‫اﻟﻌﻘﺎﻗ� ﺗﻠﻚ ﻣﻦ ﺧﻼل اﺳتﻨﻔﺎد‪ ، ERK2‬وﻟ�ﺲ ‪ERK1.‬‬ ‫ي‬ ‫ﻇﺎهﺮة إدﻣﺎن‬
‫ين‬
‫ﺑﺮوﺗن‬ ‫اﻟ�وﺗيﻨﺎت‪ ،‬ﻣﺜﻞ‬ ‫�ﺴﺘﻬﺪف �‬ ‫بﻌﻘﺎﻗ�‬
‫ي‬ ‫ّ‬
‫اﻟﻌﻘﺎﻗ� هﻮ ﺧﺎﺻ�ﺔ ﻋﺎﻣﺔ ﺗﺮﺗبﻂ بﺎﻟﻌﻼج‬ ‫ي‬ ‫أن إدﻣﺎن‬
‫ِ‬
‫ً‬ ‫�‬
‫اﻟﻌﻘﺎﻗ� �ﻤﺘﺪ أ�ﻀﺎ إ�‬
‫ي‬ ‫اﻟﻤﺜ� ا�تﺸﺎف ﻣﺎ إذا كﺎن إدﻣﺎن‬
‫ي‬ ‫‪ ،EGFR‬ي� ﻣﺴﺎر ‪ MAPK.‬وﺳ�ﻜﻮن ﻣﻦ‬
‫� َ‬
‫ﺗﺄﺷ� أﺧﺮى‪ ،‬واﻟﺘﻌﺮف ﻋ� ﻣﻜﻮﻧﺎت اﻟﻤﺴﺎر اﻟﺮﺋ�ﺴﺔ‬ ‫ي‬ ‫ات‬ ‫ر‬ ‫ﻣﺴﺎ‬ ‫ف‬ ‫ﺴﺘﻬﺪ‬
‫ِ‬ ‫�‬ ‫اﻟئ‬
‫اﻟﻌﻼﺟﺎت ي‬
‫اﻟﻤﺴﺆوﻟﺔ ﻋﻦ اﻷﻣﺮ‪.‬‬

‫‪Ali MMQE - http://translearner.weebly.com - https://www.facebook.com/Translearner‬‬

The exciting work reported by Kong et al. consists mainly of in
vitro studies, so in vivo work will be needed to examine whether
the tumour microenvironment affects drug addiction. Their study
also raises many fascinating questions: for example,why does
ERK2 but not ERK1 mediate drug addiction, even though both are
key components of the MAPK pathway. A complex network of
feedback mechanisms regulates this pathway, and the role of
these regulatory mechanisms in drug addiction should be
investigated.

The key to translating the authors' findings into clinical use will be
determining whether other drugs work better than dacarbazine if
used together with drug withdrawal to target drug-addicted cells. It
would also be useful to investigate the mechanisms that underlie
this type of synergy in greater detail. The improvements in our
understanding of drug addiction that come from this latest work
clearly offer a promising start in exploring the therapeutic
opportunities that might arise from this Achilles heel of cancer.

Ali MMQE - http://translearner.weebly.com - https://www.facebook.com/Translearner

 ‫�‬ ‫ّ‬
‫اﻟﻤﺨﺘ�‪ .‬وﻟﺬا‪،‬‬
‫�‬ ‫ﻳﺘﻜﻮن هﺬا اﻟبﺤﺚ اﻟﺸﺎﺋﻖ ﻟ�ﻮﻧﺞ وزﻣﻼﺋﻪ ‪ -‬ي� اﻷﺳﺎس ‪ -‬ﻣﻦ دراﺳﺎت ﺗﻤﺖ داﺧﻞ‬
‫ﱠ‬ ‫ﻣﻄﻠ��ﺎ إﺟﺮاء دراﺳﺎت ن� اﻟﺠﺴﻢ ّ‬ ‫ً‬
‫اﻟ�؛ ﻣﻦ أﺟﻞ اﺳﺘﻜﺸﺎف ﻣﺎ إذا كﺎﻧﺖ اﻟﺒيﺌﺔ اﻟﻤﺼﻐﺮة‬ ‫ي‬ ‫ي‬ ‫ﺳ�ﻜﻮن‬
‫�‬
‫اﻟى ﻗﺎم ﺑﻬﺎ اﻟبﺎﺣﺜﻮن‬ ‫ﻟﻠﻌﻘﺎﻗ�‪ ،‬أم ﻻ‪ .‬ي‬
‫وﺗﺜ� اﻟﺪراﺳﺔ ي‬ ‫ي‬ ‫اﻟﻤﺤ�ﻄﺔ بﺎﻟﻮرم ﺗﺆﺛﺮ ﻋ� إدﻣﺎن اﻟﺨﻼ�ﺎ‬
‫ن‬ ‫اﻟﻌﺪ�ﺪ ﻣﻦ اﻷﺳﺌﻠﺔ اﻟﻤﺜ�ة‪ ،‬ﻣﻨﻬﺎ‪ :‬ﻟﻤﺎذا ﱠ‬
‫اﻟﻌﻘﺎﻗ�‪،‬‬
‫ي‬ ‫ﻳﺘﻮﺳﻂ ‪ ERK2‬وﻟ�ﺲ ‪ ERK1‬ي� ﺣﺪوث إدﻣﺎن‬ ‫ي‬
‫�‬
‫ﻣﻜﻮﻧﺎن رﺋ�ﺴﺎن � ﻣﺴﺎر ‪MAPK‬؟ ﺗﻨﻈﻢ ﺷبﻜﺔ ﻣﻌﻘﺪة ﻣﻦ ّ‬‫ن‬ ‫رﻏﻢ أن كﻠﻴﻬﻤﺎ ﱢ‬
‫آﻟ�ﺎت ردود اﻷﻓﻌﺎل‬ ‫ي‬
‫ﻟﻠﻌﻘﺎﻗ�‪.‬‬ ‫ّ ن‬ ‫ﻔ�ض أن ﺗﺘﻢ دراﺳﺔ دور هﺬە ّ‬ ‫هﺬا اﻟﻤﺴﺎر‪ُ ،‬‬
‫و� �‬
‫ي‬ ‫اﻟﺘﻨﻈ�ﻤ�ﺔ ي� إدﻣﺎن اﻟﺨﻼ�ﺎ‬ ‫اﻵﻟ�ﺎت‬

‫اﻟ�وري‬ ‫�‬
‫إ�ﻠﻴن�ﻜ�ﺎ‪ ،‬ﺳ�ﻜﻮن ﻣﻦ ن‬ ‫ﺗﻮﺻﻞ إﻟﻴﻬﺎ اﻟبﺎﺣﺜﻮن‬ ‫اﻟئ ﱠ‬ ‫ّ‬
‫ﻗﺎبﻠ�ﺔ اﺳﺘﻐﻼل اﻟﻨﺘﺎﺋﺞ �‬ ‫وﻟﻤﻌﺮﻓﺔ‬
‫ُ ْ‬ ‫ي‬
‫ﻋﻘﺎﻗ� أﺧﺮى ﺗﻌﻤﻞ �ﺸكﻞ أﻓﻀﻞ ﻣﻦ "اﻟﺪا�ﺎر�ﺎز�ﻦ"‪ ،‬إذا اﺳﺘﺨ ِﺪ َﻣﺖ ﻣﻊ‬ ‫ي‬ ‫ﻣﻌﺮﻓﺔ ﻣﺎ إذا كﺎﻧﺖ هﻨﺎك‬
‫ً‬ ‫ُ ْ‬
‫أ�ﻀﺎ دراﺳﺔ ّ‬
‫اﻵﻟ�ﺎت‬ ‫اﻟﻤﺪ ِﻣﻨﺔ‪ ،‬أم ﻻ‪ .‬كﻤﺎ ﺳ�ﻜﻮن ﻣﻦ اﻟﻤﻔ�ﺪ‬ ‫ْﻧﻬﺞ َﺳ ْﺤﺐ اﻟﻌﻘﺎر ﻻﺳﺘﻬﺪاف اﻟﺨﻼ�ﺎ‬
‫ﱠ‬
‫اﻟﺘ َﺤ ﱡﺴﻦ ن� ْ‬ ‫ً‬ ‫اﻟ�ﺎﻣﻨﺔ وراء هﺬا اﻟﻨ�ع ﻣﻦ اﻟﺘآزر �ﺸكﻞ �‬
‫ﻓﻬﻤﻨﺎ ﻟﻈﺎهﺮة إدﻣﺎن اﻟﺨﻼ�ﺎ‬ ‫ي‬ ‫إن‬ ‫‪.‬‬‫ﺗﻔﺼ�ﻼ‬ ‫أ��‬
‫ّ‬
‫اﻟﻌﻼﺟ�ﺔ �‬ ‫�ﱢ‬ ‫ﱢ‬
‫اﻟي ﻗﺪ‬
‫ي‬ ‫اﻟﻔﺮص‬ ‫اﺳﺘﻜﺸﺎف‬ ‫ة‬ ‫ﻟﻤﺴ�‬
‫ي‬ ‫ة‬‫ﻣب�‬ ‫بﺪا�ﺔ‬ ‫م‬ ‫�ﻘﺪ‬ ‫ﻟﻠﻌﻘﺎﻗ� ‪ -‬اﻟﻨﺎﺗﺞ ﻋﻦ هﺬا اﻟﻌﻤﻞ ‪-‬‬
‫ي‬
‫ﺗنﺸﺄ بﺎﺳﺘﻐﻼل ﻧﻘﻄﺔ اﻟﻀﻌﻒ هﺬە ن ي� ﻣﺮض اﻟ�ﻃﺎن‪.‬‬

‫‪Ali MMQE - http://translearner.weebly.com - https://www.facebook.com/Translearner‬‬