Targeting PEAK1 sensitizes anaplastic thyroid carcinoma 8505C cells to BRAFV600E inhibitor Vemurafenib in vitro

Vemurafenib, one of the selective BRAF inhibitor, is less effective in BRAF-mutant thyroid cancer, including anaplastic thyroid cancer (ATC), the mechanisms of which are still lacking. Pseudopodium-enriched atypical kinase 1 (PEAK1) has been demonstrated to be upregulated in human malignancies. Enhanced PEAK1 expression facilitates tumor cell survival and chemoresistance. Here we investigated the role and mechanisms of targeting PEAK1 in reversing vemurafenib resistance in ATC 8505C cells. PEAK1 depletion alone promotes cell cycle arrest, but not affect cell apoptosis.PEAK1 depletion sensitized 8505C cells to vemurafenib by promoting cell cycle arrest and inducing cell apoptosis. Vemurafenib could quickly inhibit ERK phosphorylation (pERK1/2), but quickly reactivate pERK1/2 in 8505C cells. Vemurafenib could only quickly activate AKT phosphorylation (pAKT) and slightly activate phosphorylation JNK1/2(pJNK1/2). However, vemurafenib in combination with PEAK1 deletion inhibited reactivation of pERK1/2 and pAKT activation, and promoted pJNK1/2. Vemurafenib transiently and slightly upregulated pro-apoptotic PUMA and Bim expression, which was quickly disappeared with long time vemurafenib treatment. Combined PEAK1 depletion and Vemurafenib treatment upregulated JNK1/2-dependant Bim and AKT-dependant PUMA expression. PUMA and Bim upregulation is critical for vemurafenib induced apoptosis in presence of PEAK1 deletion. Vemurafenib resistance in 8505C cells is associated with PEAK1 activation, pERK1/2 re-activation, pJNK1/2 inactivation and AKT activation, resulting in the inhibition of AKT-dependent PUMA and pERK1/2-pJNK1/2-dependent Bim expression. PEAK1 depletion could inhibited both ERK1/2 and AKT signal and released PUMA and Bim from vemurafenib-treated cells, resulting in the enhancing cell apoptosis. Therefore, targeting PEAK1 may be an effective strategy to sensitize BRAF-mutant ATC to vemurafenib.