Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer

SIMPLE SUMMARY: Adavosertib is a first-in-class Wee1 inhibitor that has demonstrated activity against certain cancers. We evaluated the effects of adavosertib in treating differentiated thyroid cancer (DTC) using four DTC cell lines (BHP7-13, K1, FTC-133, FTC-238). Adavosertib accumulated cells in the G2/M phase and induced apoptosis in four DTC cell lines. Baseline Wee1 levels correlated with adavosertib sensitivity. Single-agent adavosertib therapy was sufficient to inhibit the growth of K1 and FTC-133 tumor models. Adavosertib potentiated the anti-tumor effect of dabrafenib and trametinib in K1 xenografts harboring the BRAF(V)(600E) mutation, with promising safety profiles. Adavosertib also improved the anti-tumor efficacy of lenvatinib in FTC-133 xenografts. Our results suggest the clinical efficacy of adavosertib for DTC patient therapy. ABSTRACT: Differentiated thyroid cancer (DTC) patients are usually known for their excellent prognoses. However, some patients with DTC develop refractory disease and require novel therapies with different therapeutic mechanisms. Targeting Wee1 with adavosertib has emerged as a novel strategy for cancer therapy. We determined the effects of adavosertib in four DTC cell lines. Adavosertib induces cell growth inhibition in a dose-dependent fashion. Cell cycle analyses revealed that cells were accumulated in the G2/M phase and apoptosis was induced by adavosertib in the four DTC tumor cell lines. The sensitivity of adavosertib correlated with baseline Wee1 expression. In vivo studies showed that adavosertib significantly inhibited the xenograft growth of papillary and follicular thyroid cancer tumor models. Adavosertib therapy, combined with dabrafenib and trametinib, had strong synergism in vitro, and revealed robust tumor growth suppression in vivo in a xenograft model of papillary thyroid cancer harboring mutant BRAF(V600E), without appreciable toxicity. Furthermore, combination of adavosertib with lenvatinib was more effective than either agent alone in a xenograft model of follicular thyroid cancer. These results show that adavosertib has the potential in treating DTC.