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
AUTHORS (35)
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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CITATIONS (35)
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