Related Experiment Video

Updated: Jul 11, 2025

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer
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Lorlatinib and capmatinib in a ROS1-rearranged NSCLC with MET-driven resistance: tumor response and evolution

Jaime L Schneider1,2, Khvaramze Shaverdashvili3,4, Mari Mino-Kenudson1,2

  • 1Massachusetts General Hospital Cancer Center and Department of Medicine, Boston, MA, 02114, USA.

NPJ Precision Oncology
|November 4, 2023
PubMed

Insights

Acquired MET amplification can drive resistance to ROS1 inhibitors in lung cancer. Combination therapy with MET inhibitors can overcome this resistance, but new resistance mechanisms may emerge.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genomics

Background:

  • Acquired drug resistance is a significant challenge in treating oncogene-driven cancers.
  • Understanding resistance mechanisms is crucial for developing effective cancer therapies.

Purpose of the Study:

  • To investigate acquired MET amplification as a resistance mechanism in ROS1-rearranged lung adenocarcinoma.
  • To evaluate the efficacy of combination therapy targeting both ROS1 and MET pathways.
  • To analyze dynamic molecular changes during sequential targeted therapy.

Main Methods:

  • Genomic and proteomic analyses of serial tumor and plasma samples.
  • Next-generation sequencing to identify genetic alterations.
  • Assessment of treatment response in intracranial and extracranial tumors.

Main Results:

  • Acquired MET amplification was identified as a resistance mechanism after ROS1 inhibitor treatment.
  • Combination therapy with lorlatinib (ROS1 inhibitor) and capmatinib (MET inhibitor) demonstrated tumor response.
  • Relapse revealed a MET D1246N mutation and loss of MET amplification, indicating polyclonal resistance.

Conclusions:

  • Sequential targeted therapies can drive complex tumor evolution and emergent resistance.
  • MET amplification is a key bypass mechanism in ROS1-rearranged lung cancer.
  • Developing strategies to prevent or overcome acquired resistance is essential for improving long-term patient outcomes.

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