Abstract P1-13-12: Targeting Dynamin-related protein 1 for the management of taxane-resistant triple-negative breast cancer

Abstract

Abstract The development of drug resistance is a primary cause of chemotherapy failure in the treatment of triple-negative breast cancer (TNBC). Some cancer cells are resistant to drugs with unrelated structures and mechanisms of action, a phenomenon known as multidrug resistance (MDR). Although taxanes such as docetaxel and paclitaxel are effective against non-metastatic and metastatic TNBC and other types of breast cancer, they eventually become ineffective due to development of drug resistance. Mitochondrial dynamics has gained significant attention as a means to treat MDR and non-MDR cancers. Mitochondrial dynamics determine the number, shape, and location of mitochondria within cells, which are fundamental to the health of the cell. Among its key components is the mitochondrial fission-promoting dynamin-related protein 1 (Drp1). There is mounting evidence indicating that both Drp1 and its phosphorylated form promote cancer survival, resistance to apoptosis, and chemoresistance. We observed increased phosphorylation of Drp1 at Ser616 as well as phosphorylation of its upstream kinase ERK1/2 in TNBC lines SUM159PT and its paclitaxel-resistant derivative that we developed called SUM159PT/PAC200 that displays more than an 80-fold increase in resistance to paclitaxel. Using CRISPR-Cas9 technology, we knocked out the gene encoding Drp1 in both lines. When Drp1 is genetically ablated, paclitaxel resistance in SUM159PT/PAC200 was significantly reversed. Furthermore, proliferation, migration, and invasion capabilities were decreased in both parental and paclitaxel-resistant Drp1 knockout lines. In SUM159PT/PAC200 Drp1-KO cells, a mesenchymal to epithelial transition (MET) was observed as indicated by downregulation of mesenchymal markers such as N-cadherin and -catenin, and upregulation of the epithelial marker ZO-1. Interestingly, Drp1 knockout halted the ability of SUM159PT/PAC200 to form colonies in soft agar. SUM159PT/PAC200 cells strongly express the MDR pump P-glycoprotein (ABCB1), to which paclitaxel is a known substrate, and genetically targeting Drp1 reduced the expression to almost undetectable levels. Taken together, these findings suggest that Drp1 is both a resistance factor and a key protein in breast cancer proliferation and dissemination, making it a promising actionable molecular target in the treatment of TNBC. Further studies are in progress to understand the role of Drp1 in the development and maintenance of MDR phenotype, proliferation, and invasion. Citation Format: David Terrero, Amit Tiwari, Dayanidhi Raman. Targeting Dynamin-related protein 1 for the management of taxane-resistant triple-negative breast cancer [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 P1-13-12.