Repurposing the third-generation EGFR inhibitor osimertinib to synergize with paclitaxel and extend survival in anaplastic thyroid cancer.

BACKGROUND: Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with limited therapeutic options and poor prognosis. This study aimed to identify effective targeted agents and evaluate their therapeutic potential in combination with paclitaxel. METHODS: High-throughput drug sensitivity and resistance screening was performed using a comprehensive library of targeted agents in ATC cells. The antitumor efficacy of selected agents was evaluated through in vitro combination studies and in vivo tumor models. Molecular mechanisms were investigated by assessing EGFR/ERK and eIF4E signaling. EGFR and eIF4E expression was quantified by ELISA in 24 pairs of matched ATC and adjacent non-tumor tissues. RESULTS: Osimertinib emerged as the most potent agent in the screening and exhibited synergistic activity with paclitaxel in vitro, with combination index values below 1.0. In vivo, osimertinib significantly inhibited tumor growth and suppressed EGFR/ERK signaling and the eIF4E-mediated translational pathway. Combination treatment markedly prolonged survival, with the last observed death occurring on Day 65, compared with 100% mortality by Day 23 in vehicle-treated controls, without observed systemic toxicity. Analysis of patient tissues revealed increased EGFR and eIF4E expression in 83% and 71% of ATC cases, respectively, with co-overexpression in 58%. CONCLUSIONS: Osimertinib demonstrates potent antitumor activity in ATC, with enhanced efficacy when combined with paclitaxel. Concurrent suppression of EGFR/ERK and eIF4E-associated signaling provides a mechanistic rationale for this combination, supporting further investigation of its therapeutic potential in ATC.