학술논문
Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution.
Document Type
Academic Journal
Author
Schneider JL; Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Shaverdashvili K; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, 15219, USA.; Department of Medicine, Division of Hematology Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.; Mino-Kenudson M; Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Digumarthy SR; Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Do A; Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Liu A; Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Gainor JF; Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Lennerz JK; Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA.; Harvard Medical School, Boston, MA, 02115, USA.; Center for Integrated Diagnostics, Department of Pathology, Massachusetts General Hospital, Boston, MA, 02114, USA.; Burns TF; University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, 15219, USA.; Department of Medicine, Division of Hematology Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.; Lin JJ; Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA. jjlin1@partners.org.; Harvard Medical School, Boston, MA, 02115, USA. jjlin1@partners.org.
Source
Publisher: Springer Nature Country of Publication: England NLM ID: 101708166 Publication Model: Electronic Cited Medium: Print ISSN: 2397-768X (Print) Linking ISSN: 2397768X NLM ISO Abbreviation: NPJ Precis Oncol Subsets: PubMed not MEDLINE
Subject
Language
English
ISSN
2397-768X
Abstract
Acquired drug resistance remains a major problem across oncogene-addicted cancers. Elucidation of mechanisms of resistance can inform rational treatment strategies for patients relapsing on targeted therapies while offering insights into tumor evolution. Here, we report acquired MET amplification as a resistance driver in a ROS1-rearranged lung adenocarcinoma after sequential treatment with ROS1 inhibitors. Subsequent combination therapy with lorlatinib plus capmatinib, a MET-selective inhibitor, induced intracranial and extracranial tumor response. At relapse, sequencing of the resistant tumor revealed a MET D1246N mutation and loss of MET amplification. We performed integrated molecular analyses of serial tumor and plasma samples, unveiling dynamic alterations in the ROS1 fusion driver and MET bypass axis at genomic and protein levels and the emergence of polyclonal resistance. This case illustrates the complexity of longitudinal tumor evolution with sequential targeted therapies, highlighting challenges embedded in the current precision oncology paradigm and the importance of developing approaches that prevent resistance.
(© 2023. The Author(s).)
(© 2023. The Author(s).)