Acquired Resistance to Drugs Targeting Tyrosine Kinases

被引:74
作者
Rosenzweig, Steven A. [1 ]
机构
[1] Med Univ South Carolina, Hollings Canc Ctr, Charleston, SC 29425 USA
来源
ADVANCES IN CANCER RESEARCH, VOL 138 | 2018年 / 138卷
关键词
GROWTH-FACTOR RECEPTOR; FACTOR-I RECEPTOR; CHRONIC MYELOID-LEUKEMIA; BREAST-CANCER CELLS; BCR-ABL; LUNG-CANCER; TRASTUZUMAB RESISTANCE; GEFITINIB RESISTANCE; ACTIVATING MUTATIONS; DOMAIN MUTATIONS;
D O I
10.1016/bs.acr.2018.02.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Resistance to chemotherapeutic drugs exemplifies the greatest hindrance to effective treatment of cancer patients. The molecular mechanisms responsible have been investigated for over 50 years and have revealed the lack of a single cause, but instead, multiple mechanisms including induced expression of membrane transporters that pump drugs out of cells (multidrug resistance (MDR) phenotype), changes in the glutathione system, and altered metabolism. Treatment of cancer patients/cancer cells with chemotherapeutic agents and/or molecularly targeted drugs is accompanied by acquisition of resistance to the treatment administered. Chemotherapeutic agent resistance was initially assumed to be due to induction of mutations leading to a resistant phenotype. While this has occurred for molecularly targeted drugs, it is clear that drugs selectively targeting tyrosine kinases (TKs) cause the acquisition of mutational changes and resistance to inhibition. The first TK to be targeted, Bcr-Abl, led to the generation of several drugs including imatinib, dasatinib, and sunitinib that provided a rich understanding of this phenomenon. It became clear that mutations alone were not the only cause of resistance. Additional mechanisms were involved, including alternative splicing, alternative/compensatory signaling pathways, and epigenetic changes. This review will focus on resistance to tyrosine kinase inhibitors (TKIs), receptor TK (RTK)-directed antibodies, and antibodies that inactivate specific RTK ligands. New approaches and concepts aimed at avoiding the generation of drug resistance will be examined. Many RTKs, including the IGF-1R, are dependence receptors that induce ligand-independent apoptosis. How this signaling paradigm has implications on therapeutic strategies will also be considered.
引用
收藏
页码:71 / 98
页数:28
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