Proto-oncogene RAS is an important clinical target in cancer; however, its role in the regulation of critical cellular processes does not favor its direct targeting for cancer therapy. Recent advances presenting evidence of cross-talk between mTORC2 and RAS, along with the ability of mTORC2 to modulate RAS-driven tumorigenesis, provide an avenue for targeting mTORC2 as an effective anti-cancer modality. We endeavored to target mTORC2 via exploiting the interaction of RAS with mSIN1, the constituent protein of mTORC2, which is important for its assembly and for its capacity to phosphorylate important cell survival proteins. We designed an 11-mer peptide (CDRI-S-016-1034) derived from RAS-Binding-Domain (RBD) of mSIN1 that directly binds to RAS, particularly at T2, E3 in the effector lobe and Q95, L159 in the allosteric lobe. Through in-solution (ITC), cell-based, ex-vivo, and in vivo studies, we successfully demonstrate that CDRI-S-016-1034 uncouples mSIN1 from RAS, thereby inhibiting mTORC2 signaling as well as its downstream cellular processes, without modulating mTORC1. Our studies present a novel first-in-class modality that selectively targets mTORC2, thereby halting cancer progression and metastatic transformation.

No abstract