Evolution of acquired resistance in a ROS1+ KRAS G12C+ NSCLC through the MAPK pathway.

TitleEvolution of acquired resistance in a ROS1+ KRAS G12C+ NSCLC through the MAPK pathway.
Publication TypeJournal Article
Year of Publication2023
AuthorsPriest K, Le A, Gebregzabheir A, Nijmeh H, Reis GB, Mandell M, Davies KD, Lawrence C, O'Donnell E, Doebele RC, Bao L, Aisner DL, Schenk EL
JournalNPJ Precis Oncol
Date Published2023 Jan 23

Patients with metastatic NSCLC bearing a ROS1 gene fusion usually experience prolonged disease control with ROS1-targeting tyrosine kinase inhibitors (TKI), but significant clinical heterogeneity exists in part due to the presence of co-occurring genomic alterations. Here, we report on a patient with metastatic NSCLC with a concurrent ROS1 fusion and KRAS p.G12C mutation at diagnosis who experienced a short duration of disease control on entrectinib, a ROS1 TKI. At progression, the patient continued entrectinib and started sotorasib, a small molecule inhibitor of KRAS p.G12C. A patient-derived cell line generated at progression on entrectinib demonstrated improved TKI responsiveness when treated with entrectinib and sotorasib. Cell-line growth dependence on both ROS1 and KRAS p.G12C was further reflected in the distinct downstream signaling pathways activated by each driver. Clinical benefit was not observed with combined therapy of entrectinib and sotorasib possibly related to an evolving KRAS p.G12C amplification identified on repeated molecular testing. This case supports the need for broad molecular profiling in patients with metastatic NSCLC for potential therapeutic and prognostic information.

Alternate JournalNPJ Precis Oncol
PubMed ID36690705
PubMed Central IDPMC9871013
Grant ListK12 CA086913 / CA / NCI NIH HHS / United States
25B1267 / / LUNGevity Foundation (LUNGevity) /
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