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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2018, Vol. 12 Issue (4) : 490-495    https://doi.org/10.1007/s11684-018-0647-7
COMMENTARY |
Taking advantage of drug resistance, a new approach in the war on cancer
Liqin Wang, Rene Bernards()
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands
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Abstract

Identification of the driver mutations in cancer has resulted in the development of a new category of molecularly targeted anti-cancer drugs. However, as was the case with conventional chemotherapies, the effectiveness of these drugs is limited by the emergence of drug-resistant variants. While most cancer therapies are given in combinations that are designed to avoid drug resistance, we discuss here therapeutic approaches that take advantage of the changes in cancer cells that arise upon development of drug resistance. This approach is based on notion that drug resistance comes at a fitness cost to the cancer cell that can be exploited for therapeutic benefit. We discuss the development of sequential drug therapies in which the first therapy is not given with curative intent, but to induce a major new sensitivity that can be targeted with a second drug that selectively targets the acquired vulnerability. This concept of collateral sensitivity has hitherto not been used on a large scale in the clinic and holds great promise for future cancer therapy.

Keywords cancer      drug resistance      genetic screens      senescence      targeted therapy     
Corresponding Authors: Rene Bernards   
Just Accepted Date: 21 June 2018   Online First Date: 19 July 2018    Issue Date: 03 September 2018
 Cite this article:   
Liqin Wang,Rene Bernards. Taking advantage of drug resistance, a new approach in the war on cancer[J]. Front. Med., 2018, 12(4): 490-495.
 URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-018-0647-7
http://academic.hep.com.cn/fmd/EN/Y2018/V12/I4/490
Fig.1  Schematic outline of the concept of synthetic lethality. Synthetic lethality refers to a genetic principle in which the combination of two genetic perturbations is lethal, whereas each individually is not. In the example shown here, only the combination of drug A and drug B is lethal to the cell, making the combination of A and B synthetic lethal.
Fig.2  Alternative drug administration schedules. Intermittent dosing uses regular “drug holidays” in which the patient is not exposed to drug. Cancer cells that have developed resistance to a cancer drug may be at a selective disadvantage in the absence of drug, leading to a decline in the fraction of drug resistant cells in this drug holiday. This should result in increased response when the drug is given again, as the fraction of drug sensitive cells should have increased during the drug holiday.
Fig.3  A one-two punch model for cancer therapy. Pro-senescence drugs can be used to induce a stable proliferation arrest associated with the onset of senescence in cancer cells. A subsequent therapy with agents that kill senescent cells (senolytic drugs) can then be applied to selectively eradicate the senescent cancer cells. Note that the proliferating cancer cells are not sensitive to the senolytic agents, which makes a sequential (or concomitant) treatment schedule necessary.
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