Pancreatic Cancer Interception with RAS Inhibition Improves Survival
Menée à l'aide de modèles murins avec mutations KRASG12D et Trp53R172H, cette étude met en évidence l'intérêt d'inhiber la GTPase RAS avant la formation d'un adénocarcinome canalaire du pancréas pour améliorer la survie
Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect at early stages, contributing to decreased survival and limited therapy options for patients. An alternative strategy to cancer treatment is cancer interception, an approach wherein therapy is administered prior to cancer diagnosis for specific populations. PDAC often arises from pancreatic intraepithelial neoplasia (PanINs) that frequently contain mutations in the oncogene KRAS. Thus, Than and colleagues investigated the potential of RAS inhibitor (RASi) interception to prolong survival in a preclinical model of PDAC. KrasG12D and Trp53R172H mutant (KPC) mice were treated with either a pan- (RMC-7977) or G12D-specific (RMC-9945) RASi prior to tumor formation. Following 10 daily doses of RASi, mice demonstrated reduced preneoplastic lesions, with similar results in a 3D histology–based pancreatic reconstruction model. Analysis of PanINs at an intermediate time point revealed decreased MAPK signaling and increased apoptosis with RAS inhibition. In line with prior studies describing remodeling of the tumor microenvironment after RAS inhibition, treated mice had fewer F4/80+ macrophages and reduced immune infiltration surrounding PanINs. To investigate long-term effects on survival, mice were exposed to a RASi or vehicle for 28 days followed by observation. While all mice eventually developed tumors, RAS inhibition significantly delayed tumorigenesis and improved overall survival, with RMC-9945 showing more robust effects compared to RMC-7977. Analysis of tumors that formed following either vehicle or RASi interception showed similar growth rates, suggesting that treatment did not promote more aggressive tumors. To further interrogate the durability of therapeutic impact, mice were subjected to a dosing schedule of 1 week on/1 week off drug. RAS inhibition again led to delayed tumor onset, tripling survival compared to controls. Moreover, RMC-7977 maintained suppression of preneoplastic lesions without disrupting pancreatic architecture. In assessing a genetic basis for tumor escape and growth following RASi treatment, whole genome sequencing revealed no differential copy number changes between treatment regimens. Together, these data support RAS inhibition as a viable precancer treatment strategy to reduce neoplastic burden and enhance overall survival in pancreatic cancer, providing compelling proof-of-concept for cancer interception.
Cancer Discovery , résumé, 2026