2. Academic Validation
  3. Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14-Mutant NSCLC

Molecular Mechanisms of Acquired Resistance to MET Tyrosine Kinase Inhibitors in Patients with MET Exon 14-Mutant NSCLC

  • Clin Cancer Res. 2020 Jun 1;26(11):2615-2625. doi: 10.1158/1078-0432.CCR-19-3608.
Gonzalo Recondo 1,  Magda Bahcall 1 2,  Liam F Spurr 3 4,  Jianwei Che 5 6,  Biagio Ricciuti 1,  Giulia C Leonardi 1,  Ying-Chun Lo 7,  Yvonne Y Li 3 4,  Giuseppe Lamberti 1,  Tom Nguyen 1,  Marina S D Milan 1,  Deepti Venkatraman 1,  Renato Umeton 8 9,  Cloud P Paweletz 2,  Adem Albayrak 8,  Andrew D Cherniack 3 4,  Kristin S Price 10,  Stephen R Fairclough 10,  Mizuki Nishino 11,  Lynette M Sholl 7,  Geoffrey R Oxnard 1,  Pasi A Jänne 1 2,  Mark M Awad 12
Affiliations

Affiliations

  • 1 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
  • 2 Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 3 Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 4 Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
  • 5 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 6 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts.
  • 7 Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 8 Department of Informatics and Analytics, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 9 Massachusetts Institute of Technology, Cambridge, Massachusetts.
  • 10 Guardant Health, Redwood City, California.
  • 11 Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
  • 12 Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts. [email protected].
PMID: 32034073 DOI: 10.1158/1078-0432.CCR-19-3608
Abstract

Purpose: Molecular mechanisms of acquired resistance to MET tyrosine kinase inhibitors (TKI) are poorly understood. We aimed to characterize the genomic mechanisms of resistance to type I and type II MET TKIs and their impact on sequential MET TKI therapy outcomes in patients with metastatic MET exon 14-mutant NSCLC.

Experimental design: Genomic alterations occurring at the time of progression on MET TKIs were studied using plasma and tissue next-generation sequencing (NGS).

Results: A total of 20 patients had tissue or plasma available for analysis at the time of acquired resistance to a MET TKI. Genomic alterations known or suspected to be mechanisms of resistance were detected in 15 patients (75%). On-target acquired mechanisms of resistance, including single and polyclonal MET kinase domain mutations in codons H1094, G1163, L1195, D1228, Y1230, and high levels of amplification of the MET exon 14-mutant allele, were observed in 7 patients (35%). A number of off-target mechanisms of resistance were detected in 9 patients (45%), including KRAS mutations and amplifications in KRAS, EGFR, HER3, and BRaf; one case displayed both on- and off-target mechanisms of resistance. In 2 patients with on-target resistant mutations, switching between type I and type II MET TKIs resulted in second partial responses.

Conclusions: On-target secondary mutations and activation of bypass signaling drive resistance to MET TKIs. A deeper understanding of these molecular mechanisms can support the development of sequential or combinatorial therapeutic strategies to overcome resistance.

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