Combinatorial Inhibition of mTORC2 and Hsp90 Leads to a Distinctly Effective Therapeutic Strategy in Malignant Pheochromocytoma

Abstract

Background: Malignant pheochromocytoma (mPCC) is an uncommon tumor with poor prognosis, and no effective therapeutic strategy exists as yet. Discovering new and effective therapeutic strategies to improve prognosis is an urgent need. Objective: To investigate whether a combinatorial inhibition of both mTORC2 and Hsp90 in PC12 cells could lead to a distinct anti-tumor effect in vitro and in vivo that was greater than the 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 distinct anti-tumor effect in vitro that was greater than the inhibition of mTORC2 or Hsp90 alone. Inhibiting Hsp90 specifically could inhibit tumor growth of sh-Rictor cells in vivo, suggesting that the combinatorial inhibition of both mTORC2 and Hsp90 could lead to a distinct anti-tumor effect in vivo. Western blotting has shown that both p-Akt Ser473 and p-Akt Thr450 showed significantly decreased expression after targeting mTORC2, while p-Akt Thr308 did not. However, all three different p-AKTs, including p-Akt Ser473, p-Akt Thr450 and p-Akt Thr308, showed a significantly decreased expression in combinatorial inhibition of both mTORC2 and Hsp90. Collectively, it revealed that combinatorial inhibition of mTORC2 and Hsp90 could destabilize the Akt signaling. Conclusion: Our results demonstrated that combinatorial inhibition of mTORC2 and Hsp90 could increase their anti-tumor effect and destabilize the Akt signaling in PC12 cells, suggesting a combinatorial inhibition of both mTORC2 and Hsp90 which might be an effective therapeutic strategy for mPCC.