Targeting focal adhesion kinase to mitigate hepatotoxicity induced by PD-1 inhibition with or without KRAS G12C suppression.

Abstract

e14597 Background: Although PD-1 antibodies exhibit significant therapeutic potential, their clinical utility is often constrained by substantial liver toxicity. Recent advancements have highlighted the potent antitumor efficacy of targeting KRAS G12C in KRAS G12C-mutant cancers. To enhance therapeutic outcomes, combination therapies integrating KRAS G12C inhibition with PD-1 blockade have been developed, demonstrating encouraging clinical results. However, this dual therapeutic approach has been linked to heightened hepatotoxicity compared to monotherapy. Our prior research revealed that FAK targeting synergistically augments antitumor effects when combined with KRAS G12C inhibition, irrespective of PD-1 antibody use. In this study, we elucidate the pivotal role of FAK signaling in hepatotoxicity induced by PD-1 blockade, with or without KRAS G12C inhibition. We further demonstrate that FAK inhibition via Ifebemtinib (Ifebe, IN10018) can alleviate drug-induced liver toxicity in preclinical models. Methods: Hepatotoxicity models were established in human PD-1 overexpressed mice through prolonged treatment with Nivolumab or AMG510-Nivolumab. Nivolumab was administered at 35 mg/kg weekly via tail vein injection, while AMG510 was given at 60 mg/kg daily via oral gavage. Ifebe was administered at 25 mg/kg daily via oral gavage. Serum samples were collected to assess biomarker levels, and liver tissues were harvested for hematoxylin and eosin (HE) staining at the study's conclusion. Results: In hPD-1 mouse models, liver toxicity induced by Nivolumab or Nivolumab-AMG510 dual therapy was significantly mitigated by the clinical-stage FAK inhibitor Ifebe. This was evidenced by a marked reduction in liver toxicity biomarkers. HE staining further corroborated that the combination of IN10018 with Nivolumab or Nivolumab-AMG510 dual therapy ameliorated hepatotoxicity induced by the anticancer agents. Conclusions: FAK inhibition with Ifebe effectively reduces liver toxicity associated with KRAS G12C inhibition and PD-1 antibody therapy, underscoring the need for further clinical investigation.