Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with few therapeutic options. The majority of patients with PDAC harbor a mutation in the KRAS oncogene. Kemp and colleagues utilized a small-molecule inhibitor of KrasG12D, MRTX1133, and identified deep tumor regressions in multiple immune-competent PDAC models. Additionally, inhibition of KrasG12D remodeled the tumor microenvironment from an immune-suppressive to an immune-reactive state with increased infiltration of M1-like macrophages and cytotoxic T cells. These results provide preclinical evidence for the efficacy of KrasG12D inhibition in PDAC and suggest MRTX1133 has the potential for translation to the clinic.

See article, p. 298.

While tumors with mismatch-repair deficiency (MMRd) all have high mutation burdens, only a fraction of patients respond to PD-1 checkpoint blockade. In a cohort of patients receiving pembrolizumab for MMRd endometrial cancer, Chow, Michaels, and colleagues found that the underlying molecular mechanism of MMRd was associated with treatment...

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