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Study identified source of crizotinib resistance in ALK-positive lung cancer
Doebele RC.Clin Cancer Res. 2012;doi:10.1158/1078-0432.CCR-11-2906.
Somatic kinase domain mutations, gene fusion and the emergence of separate oncogenic drivers are factors responsible for the observed crizotinib resistance in anaplastic lymphoma kinase-positive advanced non–small cell lung cancer, according to study results published in Clinical Cancer Research.
Based on previous studies reporting on the acquired drug resistance common among patients receiving crizotinib (Xalkori, Pfizer), researchers from the University of Colorado Cancer Center analyzed tissue obtained from 14 patients with anaplastic lymphoma kinase (ALK)-positive NSCLC, specifically those who had observed radiologic progression while receiving crizotinib, to identify the mechanisms of intrinsic and acquired resistance.
The patient group underwent 15 re-biopsy procedures after radiologic evidence of disease progression/lack of response on crizotinib; diagnostic biopsies were used as the pre-crizotinib (baseline) sample for comparison within the study. Two patients were biopsied after disease progression at the first evaluation on crizotinib and represented the intrinsic resistance demographic, whereas 12 patients underwent biopsy after initial benefit, then progression after median time on crizotinib of 8.9 months, and were categorized to represent acquired resistance demographic.
According to the study results, only 11 patients possessed material evaluable for molecular analysis. Of these, four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK; a unique mutation, encoding a G1269A amino acid substitution that produces resistance to crizotinib in vitro, was identified in two of these cases. From the remainder of the study population, two patients demonstrated a new onset ALK copy number gain; two patients exhibited a KRAS mutation, one of which occurred without evidence of a persisting ALK gene rearrangement; one patient exhibited outgrowth of EGFR mutant NSCLC without evidence of a persistent ALK gene rearrangement; one patient demonstrated the emergence of an ALK gene fusion negative tumor compared with the baseline sample, but with no identifiable alternate driver; and two patients retained ALK positivity with no identifiable resistance mechanism.
Based on these findings, researchers have expanded the possible source of ALK-positive NSCLC beyond ALK kinase domain mutations to include separate oncogene drivers and ALK gene fusion copy number gain as contributors to crizotinib resistance.
“We know that crizotinib brings ALK positive lung cancer under control for most patients. We wanted to learn how the cancer mutates so we can better treat it once it returns,” researcher Robert C. Doebele, MD, PhD, said in a press release. “The mutations we documented show us once again that we can’t treat cancer as one disease. Cancer is as individual as our patients.”
Disclosure: The researchers reported financial support from University of Colorado Lung Cancer SPORE grant, Eli Lilly & Co. and the Boettcher Foundation’s Webb-Waring Biomedical Research Program.
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The last decade has seen a revolution in the way oncologists think about lung cancer. We have rejected the old complacency of labeling nearly 190,000 patients per year as “non-small cell lung cancer.” The age of molecular profiling having relevance for treatment considerations has arrived with the selection of EGFR inhibitors for EGFR mutant lung cancers, and crizotinib for the treatment of ALK rearranged cancers. Some of the first questions that arise after an effective therapy has been developed are: When will this patient become resistant to this currently effective therapy? What is the mechanism of resistance? What strategies can be developed to either avoid resistance, to treat primary resistant disease, or to treat disease once secondary resistance arises?
Doebele and colleagues have made a major step in understanding mechanisms of resistance to crizotinib. They obtained repeat biopsies at the time of progression from 14 patients with ALK-positive lung cancers who demonstrated radiographic progression. Eleven samples had evaluable material. Of these four had secondary mutations within the tyrosine kinase domain of ALK (including two with a not before described mutation encoding G1269A missense mutation. Two patients (including one that also had a kinase domain mutation) had ALK copy number gain. One patient had the outgrowth of an EGFR mutant NSCLC, two had KRAS mutations (one in the absence of persistence of the previously found ALK rearrangement), one had outgrowth of an ALK negative tumor, and two retained ALK positivity with no identifiable resistance mutation. Interestingly enough, these clinical data are, in part, consistent with previously described in vitro data in which investigators developed crizotinib resistant lung cancer cell lines by exposing cells to increasing doses of crizotinib over a prolonged period and showing the development first of ALK amplification, and subsequently the development of a secondary mutation (with high level resistance).
Further work will obviously need to confirm these results in additional patients and to develop clinical strategies to deal with resistance. This manuscript is analogous to that reported by Sequist and colleagues last year showing the molecular evolution of EGFR mutant lung cancers by performing repeat biopsies (upon progression) in 37 patients and will undoubtedly be a guidepost for future translational work.
Greg Otterson, MD
Co-director of Thoracic Oncology, Division of Medical Oncology
Ohio State University Comprehensive Cancer Center
Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
Columbus, Ohio
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