Inhibition of Mtorc1/2 and DNA-PK via CC-115 Synergizes with Carboplatin and Paclitaxel in Lung Squamous Cell Carcinoma

Only a small percentage (< 1%) of patients with late-stage lung squamous cell carcinoma (LUSC) are eligible for targeted therapy. Because PI3K/AKT/mTOR signaling, particularly Phosphatidylinositol 3-kinase CA (PIK3CA), is dysregulated in two-thirds of LUSC, and DNA damage response pathways are enriched in LUSC, we tested whether CC-115, a dual mTORC1/2 and DNA-PK inhibitor, sensitizes LUSC to chemotherapy. We demonstrate that CC-115 synergizes with carboplatin in six of 14 NSCLC cell lines, primarily PIK3CA-mutant LUSC. Synergy was more common in cell lines that had decreased basal levels of activated AKT and DNA-PK, evidenced by reduced P-S473-AKT, P-Th308-AKT, and P-S2056-DNA-PKcs. CC-115 sensitized LUSC to carboplatin by inhibiting chemotherapy-induced AKT activation and maintaining apoptosis, particularly in PIK3CA-mutant cells lacking wild -type (WT) TP53. In addition, pathway analysis revealed that enrichments in the IFNa and IFNy pathways were significantly associated with synergy. In multiple LUSC patient-derived xenograft and cell line tumor models, CC-115 plus platinum-based doublet chemotherapy significantly inhibited tumor growth and increased overall survival as compared with either treatment alone at clinically relevant dosing schedules. IHC and immunoblot analysis of CC-115-treated tumors demonstrated decreased P-Th308-AKT, P-S473-AKT, P-S235/236-S6, and P-S2056-DNA-PKcs, showing direct pharmacodynamic evidence of inhibited PI3K/AKT/mTOR signaling cascades. Because PI3K path-way and DNA-PK inhibitors have shown toxicity in clinical trials, we assessed toxicity by examining weight and numerous organs in PRKDC-WT mice, which demonstrated that the combination treatment does not exacerbate the clinically accepted side effects of standard-of-care chemotherapy. This preclinical study pro-vides strong support for the further investigation of CC-115 plus chemotherapy in LUSC.

Automated summary

CC-115 shows synergy with carboplatin in certain types of late-stage lung squamous cell carcinoma (LUSC) cells, enhancing the effectiveness of chemotherapy by inhibiting the activation of the PI3K/AKT/mTOR signaling pathway.