Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer

Proto-Oncogene Proteins p21(ras) Multidisciplinary Lung Neoplasms Drug Resistance, Neoplasm Carcinoma, Non-Small-Cell Lung Mutation 610 Humans 600 Biomedicine and Life Sciences Antiviral Agents beta Catenin 3. Good health
DOI: 10.1126/sciadv.ade3816 Publication Date: 2023-10-13T17:58:24Z
ABSTRACT
Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that in isogenic cells correlated with increased expression of integrin β4 (ITGB4), component the focal adhesion complex. Silencing ITGB4 tolerant improved sensitivity, while overexpressing enhanced tolerance by supporting AKT-mTOR bypass signaling. Chronic treatment induced WNT and activated WNT/β-catenin signaling pathway. Thus, silencing both β-catenin significantly sensitivity tolerant, acquired, inherently resistant cells. In addition, proteasome inhibitor carfilzomib (CFZ) exhibited synergism down-regulating expression. Furthermore, adagrasib phenocopies combination effect CFZ suppressing KRAS activity inhibiting cell cycle progression Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying propose promising strategy overcome resistance.
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