Abstract 2680: Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast cancer

Abstract

Abstract Metastasis represents a therapeutic challenge, especially in the case of triple negative breast cancer (TNBC), where patients often show recurrence and metastasis due to resistance to chemotherapy. The frontline therapy in TNBC is Paclitaxel, which targets actively dividing cells inducing subsequent apoptosis. Since dormant cells or metastatic cancer cells are not targeted by Paclitaxel, this strategy selects for non-dividing stem cells or more motile metastatic cells. Therefore, targeted treatment options are needed to overcome the recurrence and spreading of metastatic cells. We recently reported on MBQ-167, a Rac/Cdc42 inhibitor, which is highly effective in reducing tumor growth and metastasis in mouse models of TNBC (Cruz-Collazo et al., 2021, Molecular Cancer Therapeutics). Unpublished data show that in the MDA-MB-231 human TNBC model, MBQ-167 is as effective as Paclitaxel in reducing tumor growth and is more effective in metastasis prevention. Therefore, we hypothesize that MBQ-167 is a viable candidate for combined therapy with Paclitaxel and will reduce metastasis in TNBC. The purpose of this study is to test MBQ-167 in combination with Paclitaxel in the EGFR overexpressing MDA-MB-468 human TNBC cell line, which is highly malignant and also expresses the Rac1.B oncogenic splice variant. We found that MBQ-167 inhibits Rac, Rac1.B, and Cdc42 activation in this cell line. Next, we tested individual or combined MBQ-167 (50 mg/kg 5X a week) via oral administration and Paclitaxel (10 mg/kg 1X a week) via intraperitoneal administration in SCID mice bearing luciferase-tagged MDA-MB-468 tumors. Tumor growth and metastases were analyzed by chemiluminescence imaging followed by H&E staining of extracted lungs at necropsy. Similar to our studies with the syngeneic 4T-1/Balb/C model, in this MDA-MB-468 model, Paclitaxel increased metastasis while single agent MBQ-167 significantly reduced metastasis. MBQ-167 in combination with Paclitaxel reduced the enhanced lung metastasis in response to Paclitaxel. In conclusion, this study validates the clinical testing of MBQ-167 in combination with Paclitaxel as a potential combination therapy for TNBC. Citation Format: Ailed M. Cruz-Collazo, Nilmary Grafals, Luis D. Borrero, Suranganie Dharmawardhane. Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2680.