KRAS Inhibition Reverses Chemotherapy Resistance Promoted by Therapy-Induced Senescence-like in Pancreatic Ductal Adenocarcinoma

BackgroundEmerging evidence suggests that chemotherapy can accumulate senescent-like cells within tumor tissues, a phenomenon linked to therapy resistance. The aim of this study is to analyze the senescence-like state of after-treatment persistent cells associated with KRAS mutational status to offer a therapeutic strategy to target these cells in pancreatic ductal adenocarcinoma (PDAC). Experimental DesignThree commercial cell lines and five patient-derived primary cell cultures with different KRAS statuses were studied following gemcitabine treatment. Senescence-like status was assessed using SA-{beta}-gal, together with cell cycle regulators such as p21. Additionally, KRAS mutations were modulated using MRTX1133 and AMG-510, and the signaling pathways ERK and AKT were analyzed and modulated in vitro. Finally, p21 expression, associated with the senescence-like state, on patient outcomes and treatment response was analyzed in publicly available bulk RNA-seq and single-nucleus datasets. ResultsWe observed an overexpression of p21 alongside an increase in SA-{beta}-gal signal in response to gemcitabine treatment, indicating the induction of a senescence-like state. Specific inhibition of KRAS G12D or G12C mutations reduced SA-{beta}-gal signal and sensitized PDAC cells to gemcitabine. Moreover, ERK inhibition but not AKT inhibition decreased SA-{beta}-gal signal. Additionally, we characterized p21 expression levels in relation to patient outcomes and found that they are modulated by treatment. ConclusionsThis dual-targeted therapeutic strategy holds promises for overcoming the challenges posed by KRAS-driven cancers, particularly in addressing the formidable obstacle of pancreatic cancer. Highlights The accumulation of senescent-like cells in tumor tissues because of chemotherapy is linked to treatment resistance, specifically in pancreatic ductal adenocarcinoma (PDAC). Therapy-induced senescence-like in PDAC is influenced by the mutational status of KRAS, affecting the response to chemotherapeutic agents. The expression of the p21 is activated in response to therapy-induced senescence-like, particularly after gemcitabine treatment and is associated with patients outcome. Specifically inhibiting the mutated form of KRAS with small compounds can sensitize PDAC cells to gemcitabine and reduce SA-{beta}-gal signal, acting through the ERK pathway but not the AKT pathway. The study presents a dual-targeted therapeutic strategy that combines KRAS inhibition with cytotoxic agents, potentially improving treatment efficacy and overcoming resistance in KRAS-driven cancers, such as PDAC.