Reactivating cGAS-STING Signaling by Targeting SOS1 Enhances Antitumor Immunity in NRAS-Mutant Tumors

Abstract

NRAS is commonly mutated in several different types of human cancer. NRAS-mutant tumors are aggressive and associated with poor outcomes. Although the development of targeted therapies as well as immune checkpoint inhibitors has led to a substantial improvement in the overall survival of patients with NRAS wild-type (WT) tumors, current therapies for NRAS-mutant cancers are limited. In this study, analysis of RNA sequencing data revealed a downregulation of the type I IFN response in NRAS-mutant tumors compared with NRAS WT tumors, which was associated with poor prognosis in NRAS-mutant melanoma. Knockdown of mutant NRAS, but not WT NRAS, enhanced the activation of cyclic GMP-AMP synthase (cGAS)-STING signaling. The formation of a trimeric complex between TBK1, STING, and IFN regulatory factor 3, which is required for the activation and nuclear translocation, was blocked in NRAS-mutant tumor cells. Inactivation of innate immune signaling by mutant NRAS altered cytokine production, resulting in cell autonomous and non-cell autonomous signaling to prevent tumor cell death and in evasion of tumor-immune surveillance. Screening of drugs for the ability to stimulate the release of CXCL10 revealed that SOS1 inhibitors reactivated cGAS-STING signaling in NRAS-mutant tumor cells. Importantly, combining SOS1 inhibitors with STING agonists maximized the activation of cGAS-STING signaling and elicited an increased antitumor immune response in vitro and in vivo. Overall, this study provides insights into the regulation of antitumor immunity by mutant NRAS and uncovers a potential strategy for treating NRAS-mutant cancer.

Significance: Suppression of innate immune signaling in NRAS-mutant tumors results from downregulation of the cGAS-STING axis and can be reversed using SOS1 inhibitors combined with STING agonists to restrain NRAS-mutant tumor growth.