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Gene expression changes in response to acute and chronic in vitro treatment with selpercatinib and pralsetinib in a murine Trim24-Ret cell line, TR.1

ABSTRACT: The TKIs selpercatinib and pralsetinib represent first line therapies for RET-positive lung cancer patients. Most patients exhibit responses, but treatment failure eventually occurs. To study acquired resistance in RET+ lung cancer, a novel murine lung cancer cell line was generated from C57BL/6 mice using an intratracheally injected Adeno-virus that contains Cas9 and guide RNAs targeting the Trim24 and Ret genes. This induces a gene rearrangement producing the Trim24-Ret fusion gene and the development of lung tumors. A cell line, TR.1 was derived from a resulting lung tumor. In an effort to understand how TR.1 cells respond to selpercatinib and pralsetinib, we treated TR.1 cells in vitro for 1-5 days with either 100nM selpercatinib or DMSO-control. In addition, TR.1 cells were made resistant to selpercatinib and pralsetinib through established dose-escalation in vitro until cultures that were resistant to ~500 nM TKI were established. TR.1 cells cultured in 0.1% DMSO over the same timeframe were used as controls. At each time point or condition, RNA was isolated and submitted to bulk RNA-seq. These data will allow a deeper understanding of mechanisms mediating acquired resistance in RET fusion-positive patients

ORGANISM(S): Mus musculus

PROVIDER: GSE298990 | GEO | 2026/06/04

REPOSITORIES: GEO

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Project description:RET fusions (e.g., with KIF5B, CCDC6, and NCOA4) drive subsets of non-small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC). Despite improvements in precision therapy using selective RET tyrosine kinase inhibitors (TKIs), resistance occurs and is often driven by RET-independent bypass mechanisms. SRC is a non-receptor tyrosine kinase and a well-known oncogene promoting proliferation, migration, stemness, etc. Although previous studies have implied crosstalk between RET and SRC, the anti-cancer effects of targeting SRC combined with first line RETi treatment, and their related molecular mechanisms are still not fully elucidated. Thus, we aimed to determine whether SRC inhibition enhances the anti-cancer effects of RET TKIs to create a combination strategy to treat RET fusion-positive (RET+) NSCLC and PTC. Our results showed that the SRC TKI, dasatinib, significantly enhanced the anti-cancer activities of RET TKIs in vitro. From phosphoproteomics analysis and validation assays using selective inhibitors and siRNAs, we have defined that dasatinib synergizes with RET TKIs through further suppression of PAK, AKT and S6 signaling pathways. Moreover, rescue experiments using SRC gatekeeper mutation (T341I) further validated that the combination effects between RET TKIs and dasatinib were SRC-dependent. Importantly, we also observed synergistic effects in RET+ cancer cells between RET TKIs and eCF506, a next-generation clinical SRC inhibitor with higher selectivity. Finally, both dasatinib and scF506 could restore selpercatinib sensitivity in a selpercatinib-resistant RET+ PTC cell line. Altogether, our results suggest that SRC and RET signaling crosstalk to activate RET canonical and non-canonical downstream pathways in RET+ NSCLC and PTC and that SRC inhibition has clinical potential against TKI-naïve and -resistant RET+ cancers.The experimental design for the tandem mass tag labeling was: DMSO (126, 127CC, 128C), DMSO 24 hrs. (127N, 128N, 129N), Pralsetinib 3 hrs. (129C, 130C, 131C), Pralsetinib 24 hrs. (130N, 131N, 132N), Dasatinib 3 hrs. (132C, 133C, 134C), PralDasa Combination 3 hrs. (133N, 134N, 135N). In the filenames, ID indicates expression proteomics; IMAC indicates phosphoproteomics.

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Gene expression changes in response to acute and chronic in vitro treatment with selpercatinib and pralsetinib in a murine Trim24-Ret cell line, TR.1

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