Research ArticleCancer

Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers

Science Translational Medicine  08 Feb 2012:
Vol. 4, Issue 120, pp. 120ra17
DOI: 10.1126/scitranslmed.3003316

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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.