Dataset Information

Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer.

ABSTRACT: The BRAFV600E mutation is the most common oncogenic mutation in thyroid cancer, suggesting an aggressive subtype of thyroid cancer and poor prognosis. Vemurafenib, a selective inhibitor of BRAFV600E, may provide therapeutic benefit in various cancers including thyroid cancer. However, the prevalence of drug resistance remains a challenge because of the feedback activation of the MAPK/ERK and PI3K/AKT pathways. In treating thyroid cancer cells with vemurafenib, we have detected reactivation of the MAPK/ERK signaling pathway as a result of the release of multiple receptor tyrosine kinases (RTKs) from the negative feedback of ERK phosphorylation. SHP2 is an important target protein downstream of the RTK signaling pathway. Decreasing it through SHP2 knockdown or the use of an inhibitor of SHP2 (SHP099) was found to significantly increase the early sensitivity and reverse the late resistance to vemurafenib in BRAFV600E mutant thyroid cancer cells. Overall, our findings suggest that blocking SHP2 reverses the reactivation of the MAPK/ERK signaling pathway caused by the activation of RTKs and improves the sensitivity of thyroid cancer to vemurafenib, which has potential implications for mechanism-based early combination strategies to treat thyroid cancer.

SUBMITTER: Ma W

PROVIDER: S-EPMC10266257 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer.

Ma Weike W Tian Mengran M Hu Linfei L Ruan Xianhui X Zhang Wei W Zheng Xiangqian X Gao Ming M

Journal of Cancer 20230529 9

The BRAFV600E mutation is the most common oncogenic mutation in thyroid cancer, suggesting an aggressive subtype of thyroid cancer and poor prognosis. Vemurafenib, a selective inhibitor of BRAFV600E, may provide therapeutic benefit in various cancers including thyroid cancer. However, the prevalence of drug resistance remains a challenge because of the feedback activation of the MAPK/ERK and PI3K/AKT pathways. In treating thyroid cancer cells with vemurafenib, we have detected reactivation of th ...[more]

PMID: 37325052

Similar Datasets

Project description:IntroductionAcquired resistance to BRAF inhibitor vemurafenib is frequently observed in metastatic colorectal cancer (CRC), and it is a thorny issue that results in treatment failure. As adaptive responses for vemurafenib treatment, a series of cellular bypasses are response for the adaptive feedback reactivation of ERK signaling, which warrant further investigation.ObjectivesWe identified ARF1 (ADP-ribosylation factor 1) as a novel regulator of both vemurafenib resistance and cancer metastasis, its molecular mechanism and potential inhibitor were investigated in this study.MethodsDIA-based quantitative proteomics and RNA-seq were performed to systematic analyze the profiling of vemurafenib-resistant RKO cells (RKO-VR) and highly invasive RKO cells (RKO-I8), respectively. Co‑immunoprecipitation assay was performed to detect the interaction of ARF1 and IQGAP1 (IQ-domain GTPase activating protein 1). An ELISA-based drug screen system on FDA-approved drug library was established to screen the compounds against the interaction of ARF1-IQGAP1.The biological functions of ARF1 and LY2835219 were determined by transwell, western blotting, Annexin V-FITC/PI staining and in vivo experimental metastasis assays.ResultsWe found that ARF1 strongly interacted with IQGAP1 to activate ERK signaling in VR and I8 CRC cells. Deletion of IQGAP1 or inactivation of ARF1 (ARF-T48S) restored the invasive ability induced by ARF1. As ARF1-IQGAP1 interaction is essential for ERK activation, we screened LY2835219 as novel inhibitor of ARF1-IQGAP1 interaction, which inactivated ERK signaling and suppressed CRC metastasis and vemurafenib-resistance in vitro and in vivo with no observed side effect. Furthermore, LY2835219 in combined treatment with vemurafenib exerted significantly inhibitory effect on ARF1-mediated cancer metastasis than used independently.ConclusionThis study uncovers that ARF1-IQGAP1 interaction-mediated ERK signaling reactivation is critical for vemurafenib resistance and cancer metastasis, and that LY2835219 is a promising therapeutic agent for CRC both as a single agent and in combination with vemurafenib.

Dataset Information

Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer.

Publications

Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets