Aneuploidy, a hallmark of cancer cells, poses an appealing opportunity for cancer treatment and prevention strategies. Using a cell-based screen to identify small molecules that could selectively kill aneuploid cells, we identified the compound N-[2-hydroxy-1-(4-morpholinylmethyl)-2-phenylethyl]-decanamide monohydrochloride (DL-PDMP), an antagonist of UDP-glucose ceramide glucosyltransferase. DL-PDMP selectively inhibited proliferation of aneuploid primary mouse embryonic fibroblasts and aneuploid colorectal cancer cells. Its selective cytotoxic effects were based on further accentuating the elevated levels of ceramide which characterize aneuploid cells, leading to increased apoptosis. We observed that DL-PDMP could also enhance the cytotoxic effects of paclitaxel, a standard of care chemotherapeutic agent that causes aneuploidy, in human colon cancer and mouse lymphoma cells. Our results offer pharmacological evidence that the aneuploid state in cancer cells can be targeted selectively for therapeutic purposes, or for reducing the toxicity of taxane-based drug regimens.

Background: RAS proteins play a vital role in cellular proliferation, differentiation, and survival, through their association and crosstalk with multiple pathways, the best characterized of which are the Ras/Raf/Mek/Erk and PI3K/PTEN/Akt/mTOR pathways. Activating mutations in KRAS are a hallmark of cancer. Clinical targeting of KRAS G12C mutation has demonstrated profound overall response rate (ORR) with relatively short progression-free survival (PFS). Some potential reasons for short PFS are MAPK pathway re-activation through wild type RAS and activation of PI3K/mTOR pathway, which lead to the bypass and acquired resistance to KRAS G12C inhibitors. The combination of KRAS G12C inhibitor with mTOR or ERK1/2 inhibitor might overcome drug resistance and prolong PFS. This study tested the antitumor effects induced by the combination of ATG-012, a KRAS G12C inhibitor, with SHP2 inhibitor (ET0038), ERK 1/2 kinase inhibitor (ATG-017), mTORC1/2 kinase inhibitor (ATG-008) or XPO1 inhibitor (selinexor), in preclinical tumor models. Methods: The in vivo combinations of the drugs were tested in NCI-H358 (non-small cell lung cancer) and Mia-Paca-2 (pancreatic cancer) CDX mouse model. The tumor bearing mouse were treated with vehicle control, ATG-012 (3 to 100 mg/kg, QD), ET0038 (5mg/kg, QD), selinexor (10mg/kg, MWF), ATG-017 (25mg/kg, QD), ATG-008 (10mg/kg, QD) or the combination for 18 to 27 days. Tumor size was measured twice a week and tumor growth inhibition (TGI) was evaluated compared with vehicle control group. Results: In the NCI-H358 CDX in vivo study, mono therapy with ATG-012 (10mg/kg), selinexor, or ATG-017 induced tumor growth inhibition (TGI) of 44.29%,73.71% and 80.85%, respectively on day 8 after grouping. The combination of ATG-012 and selinexor showed 84.96% TGI, while ATG-012 plus ATG-017 showed 97.13% TGI. The combinations induced continual tumor regression from day 9 to day 21.In the Mia-PaCa-2 CDX in vivo study, the mono therapy with ATG-012 (3 mg/kg) showed 65.6% TGI on day 27 after grouping, while single agent ET0038 or ATG-008 treatment induced 84.6% and 75.4% TGI, respectively. The combination of ATG-012 and ET0038 showed 119.1% TGI; and ATG-012 -ATG-008 combination showed 92.3% TGI. Conclusions: Strong in vivo synergism has been observed for the combination of a Kras (G12C) inhibitor (ATG-012) with a SHP2 inhibitor, ERK 1/2 inhibitor, mTORC1/2 inhibitor or XPO1 inhibitor, suggesting promising clinical therapeutic strategies for cancer patients carrying the KRAS G12C mutation. Citation Format: Jian Wang, Peng Chen, Ya Kong, Hui Yuwen, Bin Jiang, Linjie Tian, Bing Hou, Jay Mei, Bo Shan. Synergistic effects of the combination of Kras (G12C) with SHP2, ERK 1/2, mTORC1/2 or XPO1 inhibition for the treatment of Kras (G12C) mutated cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2679.