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Identification of EGFR and RAS Inhibitors using Caenorhabditis elegans
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Evolution of acquired resistance in a ROS1+ KRAS G12C+ NSCLC through the MAPK pathway

Katherine Priest1, Anh Le1, Amanuail Gebregzabheir1

  • 1Division of Medical Oncology, University of Colorado - Anschutz Medical Campus, Aurora, CO, USA.

NPJ Precision Oncology
|January 23, 2023
PubMed

Insights

Metastatic non-small cell lung cancer (NSCLC) patients with ROS1 fusions and KRAS mutations may not respond well to targeted therapies. Combined treatment with ROS1 and KRAS inhibitors showed limited benefit due to KRAS amplification.

Area of Science:

  • Oncology
  • Genomics
  • Molecular Biology

Background:

  • Metastatic non-small cell lung cancer (NSCLC) patients with ROS1 gene fusions typically respond well to ROS1-targeting tyrosine kinase inhibitors (TKIs).
  • Clinical outcomes can vary due to co-occurring genomic alterations, impacting treatment efficacy.
  • The presence of both ROS1 fusions and KRAS mutations presents a complex therapeutic challenge.

Purpose of the Study:

  • To report a case of metastatic NSCLC with concurrent ROS1 fusion and KRAS p.G12C mutation.
  • To investigate the therapeutic response to sequential and combined targeted therapies (entrectinib and sotorasib).
  • To explore the role of molecular profiling in guiding treatment decisions for complex NSCLC cases.

Main Methods:

  • Case report of a patient with metastatic NSCLC.
  • Treatment with entrectinib (ROS1 TKI) followed by combination therapy with entrectinib and sotorasib (KRAS p.G12C inhibitor).
  • Generation and analysis of a patient-derived cell line.
  • Molecular profiling including next-generation sequencing to identify genomic alterations and assess pathway activation.

Main Results:

  • The patient experienced limited disease control with entrectinib alone due to concurrent KRAS p.G12C mutation.
  • A patient-derived cell line showed improved sensitivity to combined entrectinib and sotorasib treatment in vitro.
  • Clinical benefit was not observed with combined therapy, potentially due to acquired KRAS p.G12C amplification detected during treatment.
  • Distinct downstream signaling pathways were activated by ROS1 and KRAS p.G12C drivers.

Conclusions:

  • Concurrent ROS1 fusions and KRAS p.G12C mutations in metastatic NSCLC can lead to poor response to single-agent TKIs.
  • Combined inhibition of ROS1 and KRAS may be a potential strategy, but acquired resistance mechanisms like amplification can limit efficacy.
  • Comprehensive molecular profiling is crucial for identifying actionable alterations and informing therapeutic strategies in metastatic NSCLC.

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