Obesity contributes to varied efficacy of non-covalent KRAS G12D inhibitor in murine models of pancreatic ductal adenocarcinoma

Pharmacological inhibition of oncogenic KRAS with agents targeting specific mutations and isoforms induces regression of pancreatic ductal adenocarcinoma (PDAC) tumors through direct cytotoxic effects and enhanced antitumor immunity mediated by cytotoxic T cells. Several of these candidates are already in advanced stages of clinical trials. However, obesity is a major risk factor for developing PDAC and a well-known driver of chronic systemic inflammation, mediated by excessive secretion of TNFalpha, IL-6, and IL-1beta, which impairs NK cell and T cell function, severely compromising immune surveillance and immune-mediated tumor cell killing. Therefore, we assessed the impact of diet-induced obesity (DIO) on the effectiveness of the mutation-specific KRAS (KRAS G12D ) inhibitor MRTX1133 in syngeneic PDAC tumor cell lines. In our study, MRTX1133 caused stable cell-cycle arrest in vitro and tumor regression in vivo in T-cell-high 2838c3 and T-cell-low 6419c5 syngeneic murine PDAC models, regardless of host body composition. Interestingly, tumors recurred after stopping treatment in DIO groups of both cell lines, but not in lean 2838c3 tumor-bearing mice. Transcriptomic analysis of tumors from these models showed a significant decrease in expression of genes related to T cells (Cd2, Cd3d, and Cd3g) and their effector functions (Cxcr6, Cxcr3, Dpp4, NKG7) in the 2838c3 model. Furthermore, multiparameter flow cytometric analysis of these tumors revealed increased PD-L1 hi CD206 + gMDSCs and reductions in CD4 + Foxp3 - and IFNgamma-producing CD8 + T cells. Additional analysis of genes involved in cancer and immune cell metabolism showed increased expression of Cd36 and Angptl4 in the MRTX1133-treated DIO 2838c3 tumor microenvironment. Based on these findings, MRTX1133 demonstrates initial efficacy in both T-cell-high and T-cell-low groups but does not produce sustained effects in the DIO 2838c3 model due to extensive obesity-driven immunometabolic reprogramming.