Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer.

Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. SIGNIFICANCE: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247.

The IL-1 family in tumorigenesis and antitumor immunity.

The IL-1 family of cytokines consists of IL-1α, IL-1ß, IL-18, IL-33, IL-36α, IL-36ß, and IL-36γ. These proteins form four signaling receptor complexes: the IL-1 receptor (IL-1R1 and IL-1RAcP), the IL-18 receptor (IL-18Rα and IL-18Rß), the IL-33 receptor (ST2 and IL-1RAcP), and the IL-36 receptor (IL-1Rrp2 and IL-1RAcP). The formation of receptor complexes is also regulated by various antagonistic molecules and decoy receptors. The IL-1 family cytokines are induced and secreted by both innate immune cells and tissue cells upon infection and tissue damage. Thus, they play a diverse role in mediating both innate and adaptive immune responses. During tumor development and cancer treatment, the expression of the IL-1 gene family is differentially regulated in tumor cells, tissue stromal cells, and immune cells in a stage specific and tissue specific manner. Like other cytokines, the IL-1 family proteins have pleiotropic functions that are dependent on diverse arrays of target cells. As a result, they play a complex role in tumorigenesis, cancer metastasis, immune suppression, and cancer immune surveillance. Here, we focus on reviewing experimental evidence demonstrating how members of the IL-1 family influence cancer development at the cellular and molecular level. The unique mechanisms of this group of cytokines make them attractive targets for new cancer therapy.