Abstract 1331: Inhibition of mitochondrial reprogramming regulated c-Src in triple-negative breast cancer activates autophagy-mediated survival mechanism
Authors: Jung Kwang Hwa , Park Jun Hyoung , Sirupangi Tirupataiah , Jia Dongya , Pudakalakatti Shivanand , Gandhi Nishant , Elswood Jessica , Putluri Vasanta , Creighton Chad J. , Porter Weston , Lewis Michael T. , Chen Xi , Putluri Nagireddy , Bhattacharya Pratip K. , Wong Lee-Jun C. , Das Gokul M. , Kaipparettu Benny A. 
Published: August 2018

c-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. Thus, understanding the mechanism of drug resistance to Src inhibition has major clinical significance in TNBC patients. The full activation of Src signature depends on the autophosphorylation at Y419 that allows the substrate to gain access. We have previously published that metastatic TNBC has high energy-dependency to mitochondrial fatty acid beta-oxidation (FAO) and FAO activate Src by inducing autophosphorylation at Y419. However, our recent analysis suggests that as observed with the Src inhibitors, treatment with FAO inhibitors only attenuate the TNBC tumor growth, but do not result in complete regression. 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. Studies using p53 knocked out TNBC cells confirmed that the autophagy-mediated resistance to Src inhibition is independent of their p53 status. Further analyses suggest that FAO and Src inhibitors increase the phosphorylation of ERK1/2 in TNBC. Treatment with MAPK/ERK inhibitors abolished the FAO or Src inhibitor-mediated autophagy activation. Validation of in vitro findings using in vivo TNBC patient-derived xenograft (PDX) models confirmed that Src inhibition enhances ERK1/2 activity and induces autophagy in TNBC. Overall, our results suggest that long-term FAO or Src inhibition results in ERK-mediated autophagy activation and therapeutic resistance in TNBC. This finding will have major therapeutic impact in the management of currently non-targetable aggressive TNBC.

Citation Format: Kwang Hwa Jung, Jun Hyoung Park, Tirupataiah Sirupangi, Dongya Jia, Shivanand Pudakalakatti, Nishant Gandhi, Jessica Elswood, Vasanta Putluri, Chad J. Creighton, Weston Porter, Michael T. Lewis, Xi Chen, Nagireddy Putluri, Pratip K. Bhattacharya, Lee-Jun C. Wong, Gokul M. Das, Benny A. Kaipparettu. Inhibition of mitochondrial reprogramming regulated c-Src in triple-negative breast cancer activates autophagy-mediated survival mechanism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1331.