SHP2 Inhibition Abrogates Adaptive Resistance to KRAS^G12C-Inhibition and Remodels the Tumor Microenvironment ofKRAS-Mutant Tumors

Abstract

KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime therapeutic goal. Recently, inhibitors (G12C-Is) that bind KRASG12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that, reflecting its action upstream of SOS1/2, SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and blocked adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. Biochemical analysis revealed enhanced suppression of ERK-, MYC-, anti-apoptotic-, and cell-cycle genes, and increased pro-apoptotic gene expression in tumors from combination-treated mice. SHP2-I/G12C-I also evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but also revealed direct inhibitory effects on angiogenesis resulting in decreased tumor vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional combination strategies for enhancing the efficacy of G12C-Is.

KRAS: A Druggable Target in Colon Cancer Patients

“…Several mechanisms have been proposed to explain the acquired resistance to KRASG12C inhibitors. Fedele et al [125] found that G12C evokes adaptive resistance in vitro and in vivo by inducing KRASG12C re-activation. Ryan et.…”

Conquering oncogenic KRAS and its bypass mechanisms

“…SHP2 inhibition (SHP2i) blunts GAB1-GRB2-SOS1 complex formation assembled by RTKs, thus interfering with RAS-GTP loading and activation [141]. Increased RAS-GDP occupancy provides a unique vulnerability to KRAS-GDP bound G12Ci, and complete engagement of KRAS G12C by ARS-1620 was observed in 1 hour compared to about 70% basal engagement rate in cells [142]. SHP2i enhances the efficacy of G12Ci, exacerbates MAPK suppression and overcomes G12Ci resistance in various cancers [33,112,118,[143][144][145][146].…”

Therapeutic Targets of KRAS in Colorectal Cancer

“…Overall, the primary oncogenic role of the SHP2 in the activation of the RAS/Raf pathway is to cause dephosphorylation of the tyrosine residues in the scaffolding proteins that result in the increased conversion of inactive RAS (RAS-GDP) to the activated RAS (RAS-GTP) [ 53 ]. This catalytic function also makes SHP2 a critical facilitator in acquired resistance of the RAS signaling reactivation, to overcome pharmacological inhibition [ 54 ]. These properties promote SHP2 inhibition as an attractive way to combat adaptive resistance, both as a monotherapy as well as and in combination with other agents such as, MEK inhibitors.…”