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

Nancy E Sealover; Patricia T Theard; Jacob M Hughes; Amanda J Linke; Brianna R Daley; Robert L Kortum

doi:10.1016/j.isci.2023.108711

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

iScience. 2023 Dec 11;27(1):108711. doi: 10.1016/j.isci.2023.108711. eCollection 2024 Jan 19.

Authors

Nancy E Sealover¹, Patricia T Theard¹, Jacob M Hughes¹, Amanda J Linke¹, Brianna R Daley¹, Robert L Kortum¹

Affiliation

¹ Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.

Abstract

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 KRAS^G12C 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.

Keywords: Biochemistry; Biochemistry methods; Cancer; Cell biology.

Abstract

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