Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers

Abstract

Most anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate–binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.

Treatment Efficacy and Resistance Mechanisms Using the Second-Generation ALK Inhibitor AP26113 in Human NPM-ALK–Positive Anaplastic Large Cell Lymphoma

“…However, despite great success, as expected from previous experience with tyrosine kinase inhibitors (TKI; refs. 21,22), the first cases of relapse due to the positive selection of mutant clones have already been detected in several Crizotinib-treated NSCLC and ALCL patients (20,(23)(24)(25)(26). To effectively overcome Crizotinib resistance, the development of second-generation ALK inhibitors is exponentially growing (27).…”

Mapping the molecular determinants of BRAF oncogene dependence in human lung cancer

“…Indeed, the use of an individual, genetically accurate patient-derived cell line has proven successful in several tumor models used recently by our group and others to discover clinically important mechanisms of resistance to targeted therapy in human tumors (4,(19)(20)(21). Continuous treatment of initially sensitive HCC364 BRAF V600E cells with vemurafenib resulted in the outgrowth of five sublines with acquired resistance (VR1-VR5, IC 50 >10 μM each) ( Fig.…”

Entrectinib, a Pan–TRK, ROS1, and ALK Inhibitor with Activity in Multiple Molecularly Defined Cancer Indications

“…A phase I/II study of crizotinib in selected ALK-positive NSCLC patients demonstrated striking clinical efficacy of the drug in this subset, with a 60% objective response rate, resulting in accelerated approval of crizotinib in 2011 by the FDA for the treatment of ALK-positive NSCLC patients (20). However, the observation that about one third of ALK-positive NSCLC patients progresses after initial clinical response to the drug due to the acquisition of secondary mutations (21)(22)(23), together with the apparently poor ability of crizotinib to reach effective concentrations beyond the blood-brain barrier (BBB; ref. 24), have prompted the clinical development of several "second-generation" ALK inhibitors, such as ceritinib (25) and alectinib (26).…”