MET exon 14-altered lung cancers and MET inhibitor resistance Journal Article
| Authors: | Guo, R.; Offin, M.; Brannon, A. R.; Chang, J.; Chow, A.; Delasos, L.; Girshman, J.; Wilkins, O.; McCarthy, C. G.; Makhnin, A.; Falcon, C.; Scott, K.; Tian, Y.; Cecchi, F.; Hembrough, T.; Alex, D.; Shen, R.; Benayed, R.; Li, B. T.; Rudin, C. M.; Kris, M. G.; Arcila, M. E.; Rekhtman, N.; Paik, P.; Zehir, A.; Drilon, A. |
| Article Title: | MET exon 14-altered lung cancers and MET inhibitor resistance |
| Abstract: | Purpose: MET tyrosine kinase inhibitors (TKIs) can achieve modest clinical outcomes in MET exon 14-altered lung cancers, likely secondary to primary resistance. Mechanisms of primary resistance remain poorly characterized and comprehensive proteomic analyses have not previously been performed. Experimental Design: We performed hybrid capture-based DNA sequencing, targeted RNA sequencing, cell-free DNA sequencing, selected reaction monitoring mass spectrometry (SRM-MS), and immunohistochemistry on patient samples of MET exon 14-altered lung cancers treated with a MET TKI. Associations between overall response rate (ORR), progression-free survival (PFS), and putative genomic alterations and MET protein expression were evaluated. Results: Seventy-five of 168 MET exon 14-altered lung cancers received a MET TKI. Previously undescribed (zygosity, clonality, whole-genome duplication) and known (copy-number focality, tumor mutational burden, mutation region/type) genomic factors were not associated with ORR/PFS (P > 0.05). In contrast, MET expression was associated with MET TKI benefit. Only cases with detectable MET expression by SRM-MS (N 1⁄4 15) or immunochemistry (N 1⁄4 22) responded to MET TKI therapy, and cancers with H-score ≥ 200 had a higher PFS than cancers below this cutoff (10.4 vs. 5.5 months, respectively; HR, 3.87; P 1⁄4 0.02). Conclusions: In MET exon 14-altered cancers treated with a MET TKI, a comprehensive analysis of previously unknown and known genomic factors did not identify a genomic mechanism of primary resistance. Instead, MET expression correlated with benefit, suggesting the potential role of interrogating the proteome in addition to the genome in confirmatory prospective trials. © 2020 American Association for Cancer Research. |
| Journal Title: | Clinical Cancer Research |
| Volume: | 27 |
| Issue: | 3 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-02-01 |
| Start Page: | 799 |
| End Page: | 806 |
| Language: | English |
| DOI: | 10.1158/1078-0432.Ccr-20-2861 |
| PROVIDER: | scopus |
| PMCID: | PMC7854494 |
| PUBMED: | 33172896 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 March 2021 -- Source: Scopus |
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