Abstract P2-01-05: MBQ-167 chemosensitizes triple-negative breast cancer cells to current chemotherapies and reduces paclitaxel-induced metastasis

Abstract

Abstract Triple-negative breast cancer (TNBC) is an aggressive and recurrent type of breast cancer that accounts for over 15% of new diagnoses yearly. Patients with TNBC have limited response to hormonal or targeted therapies due to the lack of ER, PR, and HER2. Therefore, the standard treatment for TNBC is anthracycline/taxane-based chemotherapies, paclitaxel (PXL), and doxorubicin (DOX), for which patients often develop chemoresistance. PXL, particularly, induces metastasis in TNBC patients by activating the Toll-Like Receptor 4 (TLR4)/NFkB signaling pathway. Since there are few targeted therapies for TNBC, there is an urgent need to identify new “druggable” molecular targets. The oncogenic GTPases Rac and Cdc42, and their downstream effector, p-21 Activated Kinase (PAK), play critical roles in TNBC development and metastatic cancer progression. Therefore, we developed MBQ-167 as a potent Rac/Cdc42 inhibitor that decreases tumor cell growth and metastasis in TNBC mouse models with no apparent toxicity. To test the hypothesis that inhibiting Rac/Cdc42 with MBQ-167 will chemosensitize TNBC cells to PXL and DOX, we treated TNBC human cell lines MDA-MB-231 and MDA-MB-468 with different concentrations of MBQ-167 (250 nM-500 nM), PXL (5 nM-10 nM), DOX (250 nM-500 nM), and their combinations. The efficacy of single and combined treatments was determined on cell proliferation with the MTT assay, apoptosis with the Caspase-Glo 3/7 assay, and cell migration with the wound healing assay. In addition, we evaluated the effect of single or combined MBQ-167 (per oral 50 mg/kg, 5X a week) and PXL (IP 10mg/kg, 1X a week) on tumor growth and metastasis in an orthotopic Luciferase tagged-MDA-MB-468 TNBC mouse model. Our in vitro results demonstrate that treatments with MBQ-167, PXL, DOX, and their respective combinations, decreased TNBC cell viability and increased apoptosis compared to vehicle controls. Both combination treatments reduced cell viability and increased apoptosis compared to PXL or DOX alone. Moreover, MBQ-167 was more effective than PXL at reducing MDA-MB-231 cell migration. DOX treatment did not affect cell migration, while combination treatment of DOX with MBQ-167 decreased migration. Moreover, in the mouse model, MBQ-167 significantly reduced MDA-MB-468 mammary tumor growth by 85% compared to vehicle treatments. This decrease in tumor growth was comparable to PXL treatment alone and in combination with MBQ-167. As expected, PXL treatment increased metastasis to the lungs and liver, while MBQ-167 prevented lung and liver metastases and reduced PXL-induced metastasis. Therefore, inhibiting Rac/Cdc42 with MBQ-167 improves the responses to current TNBC chemotherapies, PXL and Dox, and reduces PXL-induced metastasis, making MBQ-167 a potential adjuvant treatment against TNBC. This conclusion will be tested since we recently obtained IND approval from the US FDA for MBQ-167 and plan to conduct clinical trials in TNBC patients. Citation Format: Nilmary Grafals-Ruiz, Ailed M. Cruz-Collazo, Anamaris Torres-Sánchez, Surangani Dharmawardhane. MBQ-167 chemosensitizes triple-negative breast cancer cells to current chemotherapies and reduces paclitaxel-induced metastasis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-01-05.