Abstract 4387: Identification of new drug combinations that cooperatively target KRAS-dependent nuclear protein export to treat mutant KRAS-driven pancreatic adenocarcinoma

Abstract Metastatic pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a poor prognosis. Identifying useful drug combinations for PDAC treatment is an important 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 useful in PDAC treatment, it is likely that resistance will develop in most patients given single agent treatment. To overcome this anticipated limitation, effective drug combinations that include KRAS inhibitors will be necessary. We have recently determined in lung cancer cells that RAS facilitates the export of nuclear proteins into the cytoplasm via a mechanism independent of canonical RAS signaling pathways (Tripathi et al, Nature Cancer, 2024). This suggests that new drug combinations that cooperate with the inhibition of the RAS nuclear export function might be suitable for cancer therapy. Our preclinical PDAC studies suggest the lung cancer mechanisms are relevant to PDAC, with implications for possible new drug combinations. In PDAC lines, 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. Export of the nuclear EZH2 methyltransferase leads to methylation of the DLC1 protein, making it susceptible to 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. In the adjacent normal tissues, CPTAC indicates EZH2 protein levels are significantly lower and DLC1 protein levels are significantly higher than in the tumors. Our preclinical studies indicate that a three-drug combination consisting of a KRAS inhibitor plus AKT and SRC inhibitors have significantly more antitumor activity than the KRAS inhibitor alone. It is likely that the cooperation of the three-drug combination is attributable to the KRAS inhibitor increasing DLC1 protein levels, while the inhibitors of AKT kinase and SRC kinase reverse and prevent the direct phosphorylation and attenuation of DLC1 tumor suppressor functions by these kinases, thereby reactivating the tumor suppressor activity of DLC1 protein, which enhances the antitumor activity against PDAC with mutant KRAS. In addition to this useful three-drug combination, we are currently testing other drug combinations that take advantage of the KRAS-mediated nuclear protein export function. Citation Format: Brajendra K. Tripathi, Sophia M. Shahin, Xiaolan Qian, Marian E. Durkin, Ross Lake, James H. Doroshow, Dunrui Wang, Douglas R. Lowy. Identification of new drug combinations that cooperatively target KRAS-dependent nuclear protein export to treat mutant KRAS-driven pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4387.