Data from Reactivating cGAS–STING Signaling by Targeting SOS1 Enhances Antitumor Immunity in <i>NRAS</i>-Mutant Tumors

<div>Abstract<p>NRAS is commonly mutated in several different types of human cancer. <i>NRAS</i>-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 <i>NRAS</i> wild-type (WT) tumors, current therapies for <i>NRAS</i>-mutant cancers are limited. In this study, analysis of RNA sequencing data revealed a downregulation of the type I IFN response in <i>NRAS</i>-mutant tumors compared with <i>NRAS</i> WT tumors, which was associated with poor prognosis in <i>NRAS</i>-mutant melanoma. Knockdown of mutant <i>NRAS</i>, but not WT <i>NRAS</i>, 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 <i>NRAS</i>-mutant tumor cells. Inactivation of innate immune signaling by mutant <i>NRAS</i> 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 <i>NRAS</i>-mutant tumor cells. Importantly, combining SOS1 inhibitors with STING agonists maximized the activation of cGAS–STING signaling and elicited an increased antitumor immune response <i>in vitro</i> and <i>in vivo</i>. Overall, this study provides insights into the regulation of antitumor immunity by mutant <i>NRAS</i> and uncovers a potential strategy for treating <i>NRAS</i>-mutant cancer.</p>Significance:<p>Suppression of innate immune signaling in <i>NRAS</i>-mutant tumors results from downregulation of the cGAS–STING axis and can be reversed using SOS1 inhibitors combined with STING agonists to restrain <i>NRAS</i>-mutant tumor growth.</p></div>