Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer.
Amplified and/or mutated MET can act as both a primary oncogenic driver and as a promoter of tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC). However, the landscape of MET-specific targeting agents remains underdeveloped, and understanding of mechanisms of resistance to MET TKIs is limited. Here, we present a case of a patient with lung adenocarcinoma harboring both a mutation in EGFR and an amplification of MET, who after progression on erlotinib responded dramatically to combined MET and EGFR inhibition with savolitinib and osimertinib. When resistance developed to this combination, a new MET kinase domain mutation, D1228V, was detected. Our in vitro findings demonstrate that METD1228Vinduces resistance to type I MET TKIs through impaired drug binding, while sensitivity to type II MET TKIs is maintained. Based on these findings, the patient was treated with erlotinib combined with cabozantinib, a type II MET inhibitor, and exhibited a response.



With several structurally distinct MET inhibitors undergoing development for treatment of NSCLC, it is critical to identify mechanism-based therapies for drug resistance. We demonstrate that an acquired METD1228Vmutation mediates resistance to type I, but not type II, MET inhibitors, having therapeutic implications for the clinical use of sequential MET inhibitors. Cancer Discov; 6(12); 1334-41. ©2016 AACR.See related commentary by Trusolino, p. 1306This article is highlighted in the In This Issue feature, p. 1293.
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Magda
M
Bahcall
Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.|KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
Taebo
T
Sim
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
Cloud P
CP
Paweletz
Department of Medicine, University of Chicago, Chicago, Illinois.
Jyoti D
JD
Patel
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Ryan S
RS
Alden
Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.
Yanan
Y
Kuang
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Adrian G
AG
Sacher
Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea.
Nam Doo
ND
Kim
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Christine A
CA
Lydon
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Mark M
MM
Awad
Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Michael T
MT
Jaklitsch
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Lynette M
LM
Sholl
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. geoffrey_oxnard@dfci.harvard.edu pasi_janne@dfci.harvard.edu.|Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Pasi A
PA
Jänne
Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. geoffrey_oxnard@dfci.harvard.edu pasi_janne@dfci.harvard.edu.|Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
Geoffrey R
GR
Oxnard
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D000077192:Adenocarcinoma of Lung; D000813:Anilides / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use; D016896:Treatment Outcome
D000813:Anilides; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C558660:cabozantinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met
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