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Ref Type Journal Article
PMID (37713162)
Authors Rose MM, Nassar KW, Sharma V, Schweppe RE
Title AKT-independent signaling in PIK3CA-mutant thyroid cancer mediates resistance to dual SRC and MEK1/2 inhibition.
Journal Vol Issue Date Pages Journal Short Title
Medical oncology (Northwood, London, England) 40 10 2023 Sep 15 299 Med Oncol
URL
Abstract Text 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.

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