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J Cancer 2023; 14(9):1592-1604. doi:10.7150/jca.83853 This issue Cite

Research Paper

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

Weike Ma1#, Mengran Tian1,3#, Linfei Hu1, Xianhui Ruan1, Wei Zhang1,3, Xiangqian Zheng1, Ming Gao1,2✉

1. Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
2. Tianjin Union Medical Center, No.190 Jieyuan Road, Hongqiao District, Tianjin 300121, China.
3. School of Medicine, Nankai University, Tianjin 300071, China.
#These authors contributed equally to this work.

✉ Corresponding author: Ming Gao, (headandneck2008com); Tianjin Medical University Cancer Institute and Hospital, Huanhuxi Road, Ti-Yuan-Bei, Hexi District, Tianjin 300060, China; Tianjin Union Medical Center, Jieyuan Road, Hongqiao District, Tia More

Citation:
Ma W, Tian M, Hu L, Ruan X, Zhang W, Zheng X, Gao M. Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer. J Cancer 2023; 14(9):1592-1604. doi:10.7150/jca.83853. https://www.jcancer.org/v14p1592.htm
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Abstract

Graphic 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.

Keywords: Thyroid cancer, vemurafenib, BRAF inhibitor resistance, SHP2, combination strategy

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APA
Ma, W., Tian, M., Hu, L., Ruan, X., Zhang, W., Zheng, X., Gao, M. (2023). Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer. Journal of Cancer, 14(9), 1592-1604. https://doi.org/10.7150/jca.83853.

ACS
Ma, W.; Tian, M.; Hu, L.; Ruan, X.; Zhang, W.; Zheng, X.; Gao, M. Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer. J. Cancer 2023, 14 (9), 1592-1604. DOI: 10.7150/jca.83853.

NLM
Ma W, Tian M, Hu L, Ruan X, Zhang W, Zheng X, Gao M. Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer. J Cancer 2023; 14(9):1592-1604. doi:10.7150/jca.83853. https://www.jcancer.org/v14p1592.htm

CSE
Ma W, Tian M, Hu L, Ruan X, Zhang W, Zheng X, Gao M. 2023. Early Combined SHP2 Targeting Reverses the Therapeutic Resistance of Vemurafenib in Thyroid Cancer. J Cancer. 14(9):1592-1604.

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