The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway

Context: The phosphoinositide 3-kinase (PI3K)/Akt pathway is widely postulated to be an effective therapeutic target in thyroid cancer. Objective: The aim of the study was to test the therapeutic potential of the novel Akt inhibitor MK2206 for thyroid cancer. Design: We examined the effects of MK2206 on thyroid cancer cells with respect to the genotypes of the PI3K/Akt pathway. Results: Proliferation of thyroid cancer cells OCUT1, K1, FTC133, C643, Hth7, and TPC1, which harbored PIK3CA, PTEN, Ras, or RET/PTC mutations that could activate the PI3K/Akt pathway, was potently inhibited by MK2206 with IC ₅₀ values mostly below or around 0.5 μM. In contrast, no potent inhibition by MK2206 was seen in most of the Hth74, KAT18, SW1736, WRO, and TAD2 cells that did not harbor mutations in the PI3K/Akt pathway. The inhibition efficacy was also geneticselective. Specifically, the average inhibition efficacies were 59.2±11.3 vs. 36.4±8.8% (P=0.005) at 1μM MK2206 and 64.4±11.5 vs. 38.5±18.9% (P=0.02) at 3μM MK2206 for cells with mutations vs. cells without. The SW1736 cell, lacking mutations in the PI3K/Akt pathway, had minimal response to MK2206, but transfection with exogenous PIK3CA mutants, PIK3CA H1047R and E545K, significantly increased its sensitivity to MK2206. MK2206 also completely overcame the feedback activation of Akt from temsirolimus-induced mammalian target of rapamycin suppression, and the two inhibitors synergistically inhibited thyroid cancer cell growth. Conclusions: Our study demonstrates a genetic selectivity of MK2206 in inhibiting thyroid cancer cells by targeting the PI3K/Akt pathway, supporting a clinical trial in thyroid cancer.