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Modeling acquired TKI resistance and effective combination therapeutic strategies in murine RET+ lung adenocarcinoma.

Trista K Hinz¹, Anh T Le², Tristan Doan¹

¹Departments of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, CO.

Biorxiv : the Preprint Server for Biology

|June 12, 2025

Summary

Acquired resistance to RET inhibitors in lung cancer can be overcome by targeting MET and MAPK pathways. Combining therapies upfront, rather than sequentially, shows greater efficacy in eliminating tumors and prolonging response.

Keywords:

HGF Lung adenocarcinoma MET RET tyrosine kinase inhibitor

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Published on: June 26, 2019

Area of Science:

Oncology
Molecular Biology
Pharmacology

Background:

RET gene rearrangements drive a subset of lung adenocarcinomas (LUAD).
Approved tyrosine kinase inhibitors (TKIs) like selpercatinib improve outcomes but acquired resistance is a challenge.
Understanding resistance mechanisms is crucial for durable treatment of RET-driven LUAD.

Purpose of the Study:

To investigate acquired resistance mechanisms to selpercatinib in RET-driven LUAD.
To evaluate therapeutic strategies targeting acquired resistance.
To assess the efficacy of upfront combination therapy in RET+ LUAD models.

Main Methods:

Established murine models and cell lines (TR.1, TR.2) with TRIM24-RET fusion.
Treated tumors with selpercatinib and assessed resistance mechanisms.
Utilized MET, ERBB, MEK, and PTPN11 inhibitors in vitro and in vivo.
Evaluated combination therapy with selpercatinib and crizotinib (MET inhibitor).

Main Results:

Selpercatinib-resistant cells showed bypass signaling via MET and ERBB pathways and increased MAPK dependence.
Resistant cells upregulated genes in MET and ERBB signaling networks.
Co-treatment with crizotinib re-sensitized resistant tumors, but upfront combination therapy led to complete tumor elimination or prolonged response.

Conclusions:

Acquired resistance to RET TKIs involves MET and MAPK pathway activation.
Targeting resistance mechanisms at progression is less effective than upfront combination therapy.
Predicting and targeting dominant resistance pathways early is critical for effective treatment of RTK-driven LUAD.