To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer.Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors.In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drug-resistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo.The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer. The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.