Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers

Multiple mechanisms of crizotinib resistance were identified in lung cancer patients including new secondary ALK mutations and activation of receptor tyrosine kinases. Deciphering Drug Resistance in Lung Cancer Lung cancers harboring rearrangements of the anaplastic lymphoma kinase (ALK) gene are uniquely sensitive to inhibitors targeting this kinase. Recently, the ALK inhibitor crizotinib was approved by the U.S. Food and Drug Administration to treat patients with advanced lung cancer whose tumors carry ALK gene mutations. Although most of these tumors respond to crizotinib, resulting in tumor shrinkage, the beneficial effects of the drug last only ~10 months, and then the tumors develop resistance to the drug and start to grow again. The acquisition of drug resistance is the major hurdle limiting the clinical benefit afforded by this new drug. In their new study, Katayama and colleagues set out to determine the molecular mechanisms underlying the development of resistance to crizotinib in 18 lung cancer patients. The authors took biopsies from the tumors of the lung cancer patients who had developed resistance to crizotinib and interrogated these specimens with a variety of molecular techniques. Among the 18 cases, the researchers identified five patient tumors (28%) with alterations in the ALK gene that were the underlying cause of drug resistance. There were four different somatic mutations within the ALK gene and one case where the ALK gene was amplified. In vitro studies on cancer cell lines revealed that these mutations conferred resistance to crizotinib. These mutations showed different responses to next-generation ALK inhibitors, several of which have entered early-phase clinical development. One ALK mutation was highly resistant to all of the inhibitors examined. In addition, in half of the tumor samples, the authors discovered evidence of alternative mechanisms of resistance including activation of other tyrosine kinase receptors such as EGFR and KIT. The new work highlights the complexity of drug resistance mechanisms in lung cancer and showcases the need for a combination of therapeutics to overcome crizotinib resistance in the clinic. In addition, these findings reinforce the need to tailor therapeutic strategies to the specific underlying drug resistance mechanisms in the tumors to improve clinical outcomes. 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.