KRAS inhibition activates an actionable CD24 ‘don’t eat me’ signal in pancreas cancer

Abstract

AbstractKRASG12Cinhibitor (G12Ci) has produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the tumor biology of the KRASG12Callele and possible bypass mechanisms, we developed a novel autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12DPDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12Ctumors produced modest impact despite stimulating a ‘hot’ tumor immune microenvironment. Immunoprofiling revealed that CD24, a ‘do-not-eat-me’ signal, is significantly upregulated on cancer cells upon G12Ci treatment. Blocking CD24 enhanced macrophage phagocytosis of cancer cells and significantly sensitized tumors to G12Ci treatment. Similar findings were observed in KRASG12D-driven PDAC. Our study reveals common and distinct oncogenic KRAS allele-specific biology and identifies a clinically actionable adaptive mechanism that may improve the efficacy of oncogenic KRAS inhibitor therapy in PDAC.SignificanceLack of faithful preclinical models limits the exploration of resistance mechanisms to KRASG12Cinhibitor in PDAC. We generated an autochthonous KRASG12C-driven PDAC model, which revealed allele-specific biology of the KRASG12Cduring PDAC development. We identified CD24 as an actionable adaptive mechanisms in cancer cells induced upon KRASG12Cinhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.