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
  • 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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