Acquired Resistance to Crizotinib from ROS1 G2032R Mutation  


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The ALK inhibitor crizotinib (Xalkori) has also shown activity in lung cancers with ROS1 translocations. As recently reported by Mark M. Awad, MD, PhD, of Massachusetts General Hospital, Boston, and colleagues in The New England Journal of Medicine, a mutation conferring resistance to crizotinib was found to emerge during treatment in a patient with metastatic lung adenocarcinoma with a CD74-ROS1 rearrangement who had initially shown dramatic response to crizotinib.1

The patient, who had no mutations in KRAS or EGFR and no ALK translocation on initial evaluation, had fared poorly on first-line pemetrexed (Alimta) and carboplatin. Further testing identified a ROS1 rearrangement, and the patient was enrolled in a trial evaluating crizotinib in cancers with ROS1 rearrangements.

Progression after Response

Within 1 week of starting crizotinib, the patient had substantial reductions in dyspnea and fatigue and a substantial increase in appetite. A CT scan at 2 months showed dramatic response to treatment, but a month later, the patient’s respiratory symptoms worsened and imaging showed disease progression.

Subsequent biopsy of a resistant tumor and genetic analysis identified a mutation consisting of a glycine-to-arginine substitution at codon 2032 (G2032R) in the ROS1 kinase domain. This mutation had not been detected in the malignant cells assessed prior to crizotinib therapy.

On autopsy, all sites of disease examined had the G2032R mutation, indicating that its occurrence was an early event in the clonal expansion of crizotinib-resistant tumor cells. 

Not a Gatekeeper Mutation

Molecular analysis showed that the mutation confers resistance to ROS1 kinase inhibition through steric interference with drug binding. In contrast to the gatekeeper residue mutations for drug resistance found in ABL, EGFR, and ALK, the G2032R ROS1 mutation is located in the solvent front of the kinase domain and is analogous to the G1202R ALK mutation found in crizotinib-resistant ALK-rearranged lung cancers.

The investigators stated, “Whereas the L1196M ALK gatekeeper mutant may still be sensitive to newer ALK inhibitors, such as CH5424802, we previously found that G1202R ALK confers high-level resistance to crizotinib and to all the next-generation ALK inhibitors that were examined. In light of these observations, it may be necessary to identify novel compounds that specifically target the G1202R ALK or G2032R ROS1 mutant, to overcome the development of crizotinib resistance….” ■

Disclosure: The study was funded by Pfizer and others. For full disclosures of the study authors, visit www.nejm.org.

Reference

1. Awad MM, et al: N Engl J Med 368:2395-2401, 2013.



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