کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2120298 | 1546842 | 2015 | 17 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Fighting cancer drug resistance: Opportunities and challenges for mutation-specific EGFR inhibitors Fighting cancer drug resistance: Opportunities and challenges for mutation-specific EGFR inhibitors](/preview/png/2120298.png)
Multiple mutations in the EGFR gene are a major cause for the failure of Erlotinib and Gefitinib in the treatment of patients harboring non-small-cell lung cancer (NSCLC) who initially responded to this therapy. The development of these tyrosine kinase inhibitors (TKIs) is going back to the early 90s, where cancer was widely considered and fully treated as a disease of an organ. Fundamental gain of knowledge in cell biology in general and cancer genetics in particular led us to where we currently stand: cancer is a disease that originates in the genome. Fast and affordable gene sequencing paved the way and opened our eyes for the genetic instability of many cancers, particularly EGFR driven NSCLC. This might allow highly rational and personal therapies by aiming at a very particular wild type and mutant kinase pattern. However, the paradigm “one disease – one target – one drug” is currently challenged.Both activating and deactivating EGFR mutations are known to render the development of novel targeted drugs difficult. Among all lung adenocarcinomas, only 20% are driven by EGFR and only a subpopulation has an activating mutation (e.g. L858R), making them sensitive to first generation EGFR inhibitors. Unfortunately, most of them acquire second deactivating mutations (e.g. T790M) during treatment, leading to a complete loss of response.Are specific inhibitors of the double EGFR mutant L858R/T790M the magic bullet? Much scientific evidence but also high expectations justify this approach. Structural biology of EGFR mutants constitutes the basis for highly rational approaches. Second generation pan EGFR inhibitors inhibiting wild type (WT) and mutant EGFR like Afatinib suffer from dose-limiting adverse effects. Inhibition of WT EGFR is considered to be the culprit.Third generation EGFR inhibitors follow two strategies. Mutant selectivity and improved target residential time. These inhibitors display high mutant selectivity and irreversible binding patterns while sparing WT EGFR activity, hence enhancing tumor selectivity while minimizing adverse effects. Third generation EGFR inhibitors are still undergoing preclinical and clinical evaluation. The most advanced are Rociletinib and AZD9291 which displayed encouraging preliminary clinical phase II data regarding response and adverse effects. In the current review we show both a medicinal chemists’ approach toward the design of third generation EGFR inhibitors as well as a detailed overview of the development of EGFR inhibitors over the last decade. High interdisciplinary approaches, such as structural biology and time-resolved tumor genetics pave the way toward the development of drugs that target EGFR mutants. This might lead to highly effective targeted and personalized therapies with enhanced response rates for a minor cohort of patients which have to undergo continuous gene sequencing, hence enabling therapies with tailor-made TKIs.
Journal: Drug Resistance Updates - Volume 20, May 2015, Pages 12–28