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Published on: April 6, 2016
In situ modeling of acquired resistance to RTK/RAS-pathway-targeted therapies
Nancy E Sealover1, Patricia T Theard1, Jacob M Hughes1
1Department 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 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.
Insights
Acquired resistance to cancer therapies like osimertinib can be delayed by inhibiting SHP2 signaling. This approach resensitizes resistant cells and offers a new framework for combination therapies against oncogene-driven cancers.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Intrinsic and acquired resistance limit the effectiveness of oncogene-targeted cancer therapies.
- Developing reliable models to study acquired resistance is crucial for improving treatment strategies.
Purpose of the Study:
- To describe and validate an in situ resistance assay (ISRA) for modeling acquired resistance to RTK/RAS-pathway-targeted therapies.
- To investigate the potential of SHP2 inhibitors in overcoming osimertinib resistance in EGFR-mutated lung adenocarcinoma.
Main Methods:
- Development and application of an in situ resistance assay (ISRA).
- Modeling osimertinib resistance in EGFR-mutated lung adenocarcinoma (LUAD) cell lines.
- Testing the efficacy of SHP2 inhibitors in combination with targeted therapies.
Main Results:
- The ISRA reliably models acquired resistance to RTK/RAS-pathway-targeted therapies.
- SHP2 inhibition significantly delayed acquired osimertinib resistance and resensitized resistant cells.
- SHP2 inhibition reduced MAPK signaling by blocking enhanced activation of parallel RTKs.
Conclusions:
- In situ resistance assays are tractable tools for modeling acquired resistance to targeted cancer therapies.
- Inhibiting proximal RTK signaling with SHP2 inhibitors is a promising strategy to overcome acquired resistance.
- This framework can guide the development of synergistic drug combinations to target acquired resistance effectively.
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