Abstract P2-02-14: Metabolic regulation and drug resistance in c-Src activated triple negative breast cancer

c-Src (Src) is a proto-oncogene involved in signaling that culminates in the control of multiple biological functions. Src is also one of the most frequently upregulated pathways in triple negative breast cancer (TNBC). Dysregulation of Src has been detected in TNBC and is strongly associated with tumor metastasis and poor prognosis. However, even after promising preclinical studies, Src inhibitors did not show major clinical advantage in unselected TNBC populations. We have previously published that metastatic TNBC has high energy-dependency to mitochondrial fatty acid beta-oxidation (FAO) and FAO activates Src by inducing autophosphorylation at Y419. However, our recent analysis suggests that as observed with the Src inhibitors, TNBC tumors treated with FAO inhibitors also develop drug-resistance and continue tumor growth. Evaluation of their drug resistance mechanism revealed that while short-term inhibition of FAO or Src induces autophagic and apoptotic cell deaths, long-term inhibition results in autophagy-mediated drug resistance and survival. Further analyses suggest that FAO and Src inhibitors activate mitogen-activated protein (MAP) kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway via the induction of cellular reactive oxygen species (ROS) in TNBC. Activated MEK/ERK then induces survival pathways for drug resistance and tumor survival. Validation of in vitro findings using in vivo TNBC models confirmed that combination of FAO/Src inhibitors with MEK/ERK inhibitors can provide significant benefit to overcome the therapeutic resistance of TNBC. These findings open-up new therapeutic opportunities to manage TNBC patients with currently non-targetable metastatic tumors. Citation Format: Jung KH, Park JH, Sirupangi T, Jia D, Gandhi N, Pudakalakatti S, Elswood J, Porter W, Putluri N, Zhang XH-F, Chen X, Bhattacharya PK, Creighton CJ, Lewis MT, Rosen JM, Wong L-JC, Das GM, Osborne CK, Rimawi MF, Kaipparettu BA. Metabolic regulation and drug resistance in c-Src activated triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-02-14.