Efficacy and Biomarker Analysis of Adavosertib in Differentiated Thyroid Cancer

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 BRAFV600E, 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.

AXL, along with PROS1, is overexpressed in papillary thyroid carcinoma and regulates its biological behaviour

“…In addition, a first-in-class Wee-1 inhibitor, adavosertib, exerted a cytotoxic effect on FTC or BRAF V600E PTC in vivo and in vitro. Moreover, adavosertib can strengthen the tumour growth suppression of dabrafenib and trametinib [ 18 ]. It is worth noting that a series of patients with BRAF V600E RAIR metastatic PTC showed improvement in the progression-free or overall survival after treatment with a BRAF/MEK inhibitor [ 17 ].…”

“…AXL has also been verified to be highly expressed in anaplastic and medullary thyroid carcinoma, and research referring to AXL-targeted inhibitors in anaplastic or medullary thyroid carcinoma has yielded clinical value [15,16]. Moreover, several targeted therapies based on tyrosine kinase inhibitors (TKIs) have played a promising role in metastatic differentiated thyroid cancer, including radioactive iodine-refractory (RAIR) papillary thyroid carcinoma [17][18][19]. Having identified AXL as a tyrosine kinase family with similar attributes, we aimed to explore the PROS1-AXL-mediated TAM signaling pathway for the clinical management and prognosis of papillary thyroid cancer by providing a deeper understanding of its underlying molecular mechanisms.…”

PLK1 and FoxM1 expressions positively correlate in papillary thyroid carcinoma and their combined inhibition results in synergistic anti‐tumor effects

“…A recent study indicates that PLK1 is involved in differentiated thyroid cancer (DTC) [12], where PLK1 was shown to be up-regulated in DTC and pharmacological inhibition has reduced cells in the s-phase and increased cells in G2/M phase, and induced apoptosis in DTC cell lines [12]. FoxM1, a member of the Fox transcription factor family, plays a crucial role in the regulation of cell cycle progression via activating various genes pivotal for G1 to S and G2 to M phase transition including PLK1 [13,14].…”