无分化甲状腺癌（ATC）是一种罕见且侵袭性的疾病，90%的患者在诊断后1年内死亡。BRAF抑制剂达布拉非尼与MEK1/2抑制剂曲美替尼联合治疗的批准改善了ATC患者的总体生存率。然而，治疗抵抗仍然是一个主要问题。我们先前证明了Src抑制剂达沙替尼与MEK1/2抑制剂曲美替尼的联合抑制对BRAF和RAS突变的甲状腺癌细胞具有协同抑制生长和诱导凋亡的作用，但PIK3CA突变细胞表现出混合反应。在此，我们确定了AKT不是敏感性的主要调节因子，而是对联合达沙替尼和曲美替尼不敏感的PIK3CA突变细胞具有持续激活的PDK1信号传导。此外，PDK1和MEK1/2的联合抑制足以减少细胞存活率。这些数据表明PDK1抑制是对不响应于联合Src和MEK1/2抑制的PIK3CA突变的治疗选择。© 2023. 作者及Springer Science+Business Media, LLC, Springer Nature部分享有独家许可权。

Anaplastic thyroid cancer (ATC) is a rare and aggressive disease with 90% of patients succumbing to this disease 1 year after diagnosis. The approval of the combination therapy of a BRAF inhibitor dabrafenib with the MEK1/2 inhibitor trametinib has improved the overall survival of ATC patients. However, resistance to therapy remains a major problem. We have previously demonstrated combined inhibition of Src with dasatinib and MEK1/2 with trametinib synergistically inhibits growth and induces apoptosis in BRAF- and RAS-mutant thyroid cancer cells, however PIK3CA-mutant cells exhibit a mixed response. Herein, we determined that AKT is not a major mediator of sensitivity and instead PIK3CA-mutants that are resistant to combined dasatinib and trametinib have sustained activation of PDK1 signaling. Furthermore, combined inhibition of PDK1 and MEK1/2 was sufficient to reduce cell viability. These data indicate PDK1 inhibition is a therapeutic option for PIK3CA mutations that do not respond to combined Src and MEK1/2 inhibition.© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.