Novel inhibition of central carbon metabolism pathways by Rac and Cdc42 inhibitorMBQ-167 and paclitaxel
Triple negative breast cancer (TNBC) represents a therapeutic challenge where standard chemotherapy is limited to paclitaxel. MBQ-167, a clinical stage small molecule inhibitor that targets Rac and Cdc42, inhibits tumor growth and metastasis in mouse models of TNBC. Herein, we investigated the efficacy of MBQ-167 in combination with paclitaxel in TNBC pre-clinical models, as a prelude to safety trials of this combination in advanced breast cancer patients. Individual MBQ-167 or combination therapy with paclitaxel was more effective at reducing TNBC cell viability and increasing apoptosis compared to paclitaxel alone. In orthotopic mouse models of human TNBC (MDA-MB-231 and MDA-MB-468), individual MBQ-167, paclitaxel, or the combination reduced mammary tumor growth with similar efficacy, with no apparent liver toxicity. However, paclitaxel single agent treatment significantly increased lung metastasis, while MBQ-167, single or combined, reduced lung metastasis. In the syngeneic 4T1/BALB/c model, combined MBQ-167 and paclitaxel decreased established lung metastases by ~80%. To determine the molecular basis for the improved efficacy of the combined treatment on metastasis, 4T1 tumor extracts from BALB/c mice treated with MBQ-167, paclitaxel, or the combination were subjected to transcriptomic analysis. Gene set enrichment identified specific downregulation of central carbon metabolic pathways by the combination of MBQ-167 and Paclitaxel but not individual compounds. Biochemical validation, by immunoblotting and metabolic Seahorse analysis, shows that combined MBQ-167 and paclitaxel reduces glycolysis. This study provides a strong rationale for the clinical testing of MBQ-167 in combination with paclitaxel as a potential therapeutic for TNBC and identifies a unique mechanism of action. Overall design: BALB/c mice were injected in the 4th mammary fat pad with 300,000 mouse 4T1 mammary carcinoma cells expressing firefly luciferase on two different occasions. To determine the effect of single or combination agent treatment (under MBQ-167 and paclitaxel treatments) on the established lung metastatic burden and to perform genome wide transcriptomic analyses. For the transcriptomic analysis, BALB/c mice bearing 4T1 mouse tumors were treated on day 14 with 100 mg/kg MBQ-167 5X a week for 2 weeks and 5 mg/kg paclitaxel 1X a week. On day 28, mice were sacrificed, and the tumor extracts subjected to transcriptomic analysis.