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

KRAS ^G12C inhibitor (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 KRAS ^G12C allele and possible bypass mechanisms, we developed a novel autochthonous KRAS ^G12C -driven PDAC model. Compared to the classical KRAS ^G12D PDAC model, the G12C model exhibit slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRAS ^G12C tumors 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 KRAS ^G12D -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.

Significance: Lack of faithful preclinical models limits the exploration of resistance mechanisms to KRAS ^G12C inhibitor in PDAC. We generated an autochthonous KRAS ^G12C -driven PDAC model, which revealed allele-specific biology of the KRAS ^G12C during PDAC development. We identified CD24 as an actionable adaptive mechanisms in Cancer cells induced upon KRAS ^G12C inhibition and blocking CD24 sensitizes PDAC to KRAS inhibitors in preclinical models.