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RNA-Seq analysis of 3 month old all Ret-positive (EGFP-labeled) dorsal root ganglia L345 or L6S1 neurons

ABSTRACT: The goal of this set is to build expression data using FACS isolated Ret-positive cells harvested from a Ret-EGFP reporter mouse (3 month old). To enrich for bladder projecting neurons L6S1 DRGs were FACS isolated. L3,4, 5 lumbar levels were also FACS isolated to aid in differential expression of Ret-positive populations from L6S1 and L345 and help enrich bladder Ret-positive neurons. The series further includes these populations from males and females to uncover sex based differences.

ORGANISM(S): Mus musculus

PROVIDER: GSE74138 | GEO | 2017/09/30

SECONDARY ACCESSION(S): PRJNA299153

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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RNA-Seq analysis of 3 month old all Ret-positive (EGFP-labeled) dorsal root ganglia L345 or L6S1 neurons

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