Crizotinib resistance: Implications for therapeutic strategies

Abstract

In 2007, a chromosomal rearrangement resulting in a gene fusion leading to expression of a constitutively active anaplasticlymphoma kinase (ALK) fusion protein was identified as an oncogenic driver in non-small-cell lung cancer (NSCLC). ALKrearrangements are detected in 3%-7% of patients with NSCLC and are particularly enriched in younger patients withadenocarcinoma and a never or light smoking history. Fortuitously, crizotinib, a small molecule tyrosine kinase inhibitor initiallydeveloped to target cMET, was able to be repurposed for ALK-rearranged (ALK+) NSCLC. Despite dramatic anddurable initial responses to crizotinib; however, the vast majority of patients will develop resistance within a few years. Diverse molecular mechanisms underlie resistance to crizotinib. This review will describe the clinical activity of crizotinib, review identified mechanisms of crizotinib resistance, and end with a survey of emerging therapeutic strategies aimed atovercoming crizotinib resistance.