Details

Autor(en) / Beteiligte

• Bahcall, Magda
• Sim, Taebo
• Paweletz, Cloud P
• Patel, Jyoti D
• Alden, Ryan S
• Kuang, Yanan
• Sacher, Adrian G
• Kim, Nam Doo
• Lydon, Christine A
• Awad, Mark M
• Jaklitsch, Michael T
• Sholl, Lynette M
• Jänne, Pasi A
• Oxnard, Geoffrey R

Titel

Acquired METD1228V Mutation and Resistance to MET Inhibition in Lung Cancer

Ist Teil von

• Cancer discovery, 2016-12, Vol.6 (12), p.1334-1341

Ort / Verlag

United States

Erscheinungsjahr

2016

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 MET induces 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 MET mutation 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.