In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies

• Published in: iScience 2024-01, Vol.27 (1), p.108711-108711, Article 108711
• Main Authors: Sealover, Nancy E., Theard, Patricia L., Hughes, Jacob M., Linke, Amanda J., Daley, Brianna R., Kortum, Robert L.
• Format: Article
• Language: English
• Subjects: Biochemistry; Biochemistry methods; Cancer; Cell biology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.108711

Intrinsic and acquired resistance limit the window of effectiveness for oncogene-targeted cancer therapies. Here, we describe an in situ resistance assay (ISRA) that reliably models acquired resistance to RTK/RAS-pathway-targeted therapies across cell lines. Using osimertinib resistance in EGFR-mutated lung adenocarcinoma (LUAD) as a model system, we show that acquired osimertinib resistance can be significantly delayed by inhibition of proximal RTK signaling using SHP2 inhibitors. Isolated osimertinib-resistant populations required SHP2 inhibition to resensitize cells to osimertinib and reduce MAPK signaling to block the effects of enhanced activation of multiple parallel RTKs. We additionally modeled resistance to targeted therapies including the KRASG12C inhibitors adagrasib and sotorasib, the MEK inhibitor trametinib, and the farnesyl transferase inhibitor tipifarnib. These studies highlight the tractability of in situ resistance assays to model acquired resistance to targeted therapies and provide a framework for assessing the extent to which synergistic drug combinations can target acquired drug resistance. [Display omitted] •Acquired resistance to RTK/RAS pathway members can be modeled in situ•SHP2 inhibitors reduce the development of acquired osimertinib resistance•Isolated osimertinib-resistant populations show hyperactivation of multiple RTKs•SHP2 inhibitors resensitize resistant populations to osimertinib treatment Biochemistry; Biochemistry methods; Cell biology; Cancer