推进治疗突变KRAS驱动性胰腺腺癌的新型合理药物组合

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a poor prognosis, largely due to late diagnosis and limited response to currently available therapies. Identifying effective drug combinations that harness PDAC-specific vulnerabilities remains a major challenge for molecularly targeted therapy. Oncogenic mutations in the KRAS gene, which are found in over 90% of PDAC patients, play a critical role in PDAC. Although KRAS inhibitors may be found to be clinically useful for treating PDAC, it is likely that resistance will develop in most patients when given as single agent treatment. To overcome this anticipated limitation, effective drug combinations that include KRAS inhibitors will be necessary. We have determined in preclinical human and mouse lung cancer models that RAS facilitates the export of nuclear proteins into the cytoplasm via a mechanism independent of canonical RAS signaling (Tripathi et al., 2024, Nature Cancer ). This observation suggests that new drug combinations that cooperate with the inhibition of the RAS nuclear export function might be suitable for targeted cancer therapy. Our preclinical PDAC studies suggest that the newly identified RAS-dependent nuclear export mechanism is also relevant to PDAC and may have implications for developing new drug combinations for PDAC treatment. In human PDAC models, we have found that the DLC1 tumor suppressor protein is a critical downstream target of KRAS-dependent nuclear protein export. Perinuclear binding of KRAS-GTP to RanGAP1 promotes the hydrolysis of RAN-GTP to RAN-GDP and the consequent release of nuclear protein cargo into the cytoplasm. In human PDAC models, export of the nuclear EZH2 methyltransferase into the cytoplasm leads to methylation of the cytoplasmic DLC1 protein, making it susceptible to ubiquitin-dependent proteasomal degradation. Conversely, KRAS inhibition prevents the nuclear export of EZH2, leading to an increase in DLC1 protein levels. Consistent with these findings, analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC) database indicates DLC1 protein levels in PDAC are lower than would be expected from the relatively high DLC1 mRNA expression in these tumors. Remarkably, the low levels of DLC1 protein in PDAC are inversely correlated with the high levels of the FBXW5 E3 ubiquitin ligase. Our preclinical PDAC studies show that a three-drug combination, comprising a KRAS inhibitor plus AKT and SRC inhibitors, exhibits significantly greater antitumor activity than the KRAS inhibitor alone. The cooperative effect of the three-drug combination arises as the KRAS inhibitor increases DLC1 protein levels, while AKT and SRC kinase inhibitors block phosphorylations that attenuate DLC1 tumor suppressor activity. Mechanistically, this three-drug combination enhances antitumor effects in mutant KRAS PDAC by stabilizing and reactivating the DLC1 tumor suppressor protein.