Elsevier

Annals of Oncology

Volume 27, Supplement 3, September 2016, Pages iii42-iii50
Annals of Oncology

review
Crizotinib resistance: implications for therapeutic strategies

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ABSTRACT

Anaplastic lymphoma kinase-rearranged lung cancer is associated with significant response to crizotinib. However, resistance to crizotinib typically develops within 1-2 years. Preclinical studies and biopsies of resistant sites have demonstrated that diverse mechanisms underlie resistance. Insight into resistance mechanisms has facilitated development of next-generation inhibitors and led to therapeutic combination strategies, several of which are being tested in the clinic.

In 2007, a chromosomal rearrangement resulting in a gene fusion leading to expression of a constitutively active anaplastic lymphoma kinase (ALK) fusion protein was identified as an oncogenic driver in non-small-cell lung cancer (NSCLC). ALK rearrangements are detected in 3%–7% of patients with NSCLC and are particularly enriched in younger patients with adenocarcinoma and a never or light smoking history. Fortuitously, crizotinib, a small molecule tyrosine kinase inhibitor initially developed to target cMET, was able to be repurposed for ALK-rearranged (ALK+) NSCLC. Despite dramatic and durable 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 at overcoming crizotinib resistance.

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