Resistance mechanisms after tyrosine kinase inhibitors afatinib and crizotinib in non-small cell lung cancer, a review of the literature

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• 作者：A.J. van der Wekken^a ; ^{a.j.van.der.wekken@umcg.nl" class="auth_mail" title="E-mail the corresponding author}Author Vitae ; A. Saber^bAuthor Vitae ; T.J.N. Hiltermann^aAuthor Vitae ; K. Kok^cAuthor Vitae ; A. van den Berg^bAuthor Vitae ; H.J.M. Groen^aAuthor Vitae
• 关键词：EGFR ; ALK ; Targeted therapy ; Crizotinib resistance ; Afatinib resistance ; NSCLC
• 刊名：Critical Reviews in Oncology and Hematology
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：100
• 期：Complete
• 页码：107-116
• 全文大小：1207 K

文摘

Targeted treatment of advanced non-small cell lung cancer patients with afatinib in EGFR mutation or crizotinib in ALK break positive patients results in profound tumor responses but inevitably induces resistance. In this review we present currently known resistance mechanisms for afatinib and crizotinib two recently approved drugs.

Resistance mechanisms identified for afatinib include c-MET amplification and the V843I EGFR mutation. Expression of FGFR1, increased IL6R/JAK/STAT signaling, enhanced interference with aerobic glycolysis and autophagy are associated with resistance to afatinib. Most common resistance mechanisms for ALK break positive cases are gatekeeper mutations in the ALK gene. Also activation of the EGFR pathway, KRAS mutations, the autophagy pathway and epithelial mesenchymal transition (EMT), have been associated with resistance. Many of the proposed resistance mechanisms need to be functionally studied to proof a causative relationship with resistance.