Emergence of Preexisting MET Y1230C Mutation as a Resistance Mechanism to Crizotinib in NSCLC with MET Exon 14 Skipping

• Published in: Journal of thoracic oncology 2017-01, Vol.12 (1), p.137-140
• Main Authors: Ou, Sai-Hong Ignatius, Young, Lauren, Schrock, Alexa B., Johnson, Adrienne, Klempner, Samuel J., Zhu, Viola W., Miller, Vincent A., Ali, Siraj M.
• Format: Article
• Language: English
• Subjects: Aged; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Brain Neoplasms - secondary; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Circulating tumor DNA; Crizotinib; DNA, Neoplasm - blood; DNA, Neoplasm - genetics; Drug Resistance, Neoplasm - genetics; Exons - genetics; Female; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; MET exon 14 skipping; MET Y1230C; Mutation - genetics; Neoplasm Staging; Prognosis; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-met - genetics; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Resistance mutation
• ISSN: 1556-0864; 1556-1380
• DOI: 10.1016/j.jtho.2016.09.119

MET proto-oncogene, receptor tyrosine kinase gene exon 14 skipping (METex14) alterations represent a unique subset of oncogenic drivers in NSCLC. Preliminary clinical activity of crizotinib against METex14-positive NSCLC has been reported. The full spectrum of resistance mechanisms to crizotinib in METex14-positive NSCLC remains to be identified. Hybrid capture–based comprehensive genomic profiling performed on a tumor specimen obtained at diagnosis, and a hybrid capture–based assay of circulating tumor DNA (ctDNA) at the time of progression during crizotinib treatment was assessed in a pairwise fashion. A METex14 alteration (D1010H) was detected in the pretreatment tumor biopsy specimen, as was MET proto-oncogene, receptor tyrosine kinase (MET) Y1230C, retrospectively, at very low frequency (0.3%). After a confirmed response during crizotinib treatment for 13 months followed by progression, both MET proto-oncogene, receptor tyrosine kinase gene Y1230C and D1010H were detected prospectively in the ctDNA. Emergence of the preexisting MET Y1230C likely confers resistance to crizotinib in this case of METex14-positive NSCLC. Existence of pretreatment MET Y1230C may eventually modulate the response of METex14-positive NSCLC to type I MET tyrosine kinase inhibitors. Noninvasive plasma-based ctDNA assays can provide a convenient method to detect resistance mutations in patients with previously known driver mutations.