Crizotinib resistance: implications for therapeutic strategies

Abstract

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.

Figure 1.

Diverse mechanisms of resistance leading to systemic relapse can emerge in the setting of selective pressure exerted by crizotinib. Identified mechanisms of resistance are depicted on the right. Different patterns are seen during progression on crizotinib (depicted on the left). Progression typically involves multiple sites. Patients with ALK+ non-small-cell lung cancer who are treated with crizotinib are prone to central nervous system relapse, particularly isolated central nervous system relapse. A subgroup of patients will have oligoprogression, or relapse involving only limited sites.

Figure 2.

The anaplastic lymphoma (ALK) receptor tyrosine kinase comprises an extracellular ligand-binding domain (residues 19–1038), transmembrane domain (residues 1039–1059), and intracellular domain (residues 1060–1620). The tyrosine kinase domain is located in the cytoplasm and spans residues 1116–1392. The kinase domain includes a glycine rich (G-rich) loop (residues 1123–1128), an αC helix (residues 1157–1173), a catalytic loop (residues 1246–1251), and an activation loop (residues 1271–1288). The identified acquired secondary ALK kinase mutations conferring resistance to crizotinib are located between the G-rich loop and the activation loop. Structural modeling of these mutations suggests that crizotinib resistance is caused by increased catalytic activity of ALK or diminished affinity of crizotinib for mutant ALK.