PEAK1 attenuation sensitizes anaplastic thyroid carcinoma cells in vitro to BRAFV600E inhibitor Vemurafenib

Pseudopodium-enriched atypical kinase 1 (PEAK1) has been demonstrated to be upregulated in human malignancies and cells. Enhanced PEAK1 expression facilitates tumor cell survival and chemoresistance, and vice versa. However, the role of PEAK1 in ATC and vemurafenib resistance in ATC cells is still unknown. Here, we observed that vemurafenib could effectively and quickly inhibit ERK phosphorylation(pERK1/2), but quickly reactivate pERK1/2 in ATC cell line 8505C and SW1736 cells harboring BRAF in vitro. Vemurafenib could also quickly activate AKT phosphorylation (pAKT). Furthermore, vemurafenib transiently upregulated pro-apoptotic PUMA and Bim expression, which was quickly disappeared with long time vemurafenib treatment in both of the cells in vitro. Vemurafenib treatment upregulated PEAK1 expression; And PEAK1 depletion inhibited the cell viability, colony formation, but did not affect cell apoptosis, and vice versa in both of the cells in vitro. Furthermore, PEAP1 depletion sensitized 8505C and SW1736 cells to vemurafenib by decreasing cell viability, colony formation, but inducing cell apoptosis. Mechanistically, combined PEAK1 depletion and Vemurafenib treatment inhibited reactivation of ERK1/2 and upregulated JNK1/2-dependant Bim as well as inhibited the activation of AKT and upregulated AKT-dependant PUMA. In conclusion, vemurafenib resistance in ATC cells harboring BRAF is associated with PEAK1 activation, reactivation of ERK1/2 and activation of AKT, resulting in the inhibition of pro-apoptotic PUMA and Bim protein. PEAK1 depletion could inhibited both ERK1/2 and AKT signal and released PUMA and Bim from vemurafenib-treated cells, resulting in enhancing cell apoptosis. Therefore, targeting PEAK1 may be an effective strategy to sensitize BRAF-mutant ATC to vemurafenib.