Combinatorial inhibition of mTORC2 and Hsp90 leads to a distinctly effective therapeutic strategy in malignant pheochromocytom

BACKGROUND: Malignant pheochromocytoma (mPCC) is an uncommon tumor with poor prognosis, and no effective therapeutic strategy exists. Discovering new and effective therapeutic strategies to improve prognosis is an urgent need. OBJECTIVE: To investigate whether combinatorial inhibition of both mTORC2 and Hsp90 in PC12 cells could lead to a distinctly antitumor effect in vitro and in vivo that was greater than inhibition of mTORC2 or Hsp90 alone. METHODS: Targeting mTORC2 was assessed by knockdown of Rictor using shRNA, and 17-AAG was used to inhibit Hsp90 function. RESULTS: Combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinctly antitumor effect in vitro that was greater than inhibition of mTORC2 or Hsp90 alone. Inhibiting Hsp90 specifically could inhibit tumor growth of sh-Rictor cells in nude mice, suggesting that combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinctly antitumor effect in vivo. Western blotting shown that both p-Akt Ser473 and p-Akt Thr450 were significantly decreased expression after targeting mTORC2, while p-Akt Thr308 was not. However, all of the three different p-AKT, including p-Akt Ser473, p-Akt Thr450 and p-Akt Thr308, were significantly decreased expression when combinatorial inhibition of both mTORC2 and Hsp90. Collectively, it revealed that combinatorial inhibition of mTORC2 and Hsp90 could destabilize Akt signaling. CONCLUSIONS: Our results demonstrated that combinatorial inhibition of mTORC2 and Hsp90 could increase their antitumor effect and destabilize Akt signaling in PC12 cells, suggesting combinatorial inhibition of both mTORC2 and Hsp90 might be an effective therapeutic strategy for mPCC.