Breast cancer is the most commonly diagnosed cancer in women, claiming the lives of hundreds of thousands of women each year. Dysregulation of c Met correlates with aggressive proliferation, invasive character, and pathological motility, especially in triple negative breast cancer (TNBC). The Mediterranean diet is known to reduce the incidence of breast and colon malignancies. Extra-virgin olive oil (EVOO) represents a main ingredient in this diet. The EVOO-derived (-)-oleocanthal was shown to target the RTK c-Met. Oleocanthal selectively inhibited the proliferation, migration and invasion of several c-Met dependent breast and prostate tumor cell lines. Oleocanthal exerted potent in-vivo efficacy in an orthotopic athymic nude mouse breast cancer xenograft model much greater than its modest in-vitro potency. Several oleocanthal bioisosteres have been semisynthized of which the analog HVS have shown significant activity improvement against breast cancer in vitro and in vivo models. Selectivity profiling against a TKs panel, structurally related to c-Met, suggested the HVS has high selectivity to both Met and ABL1 kinases. Overexpression of ABL1 kinase is implicated in the progression of several solid tumors concomitantly with c-Met activation, including breast, colon, lung and other cancers. ABL1 interconnects oncogenic Met and p53 pathways and hence dual blockage of c-Met and ABL1 activation adds significant advantages over currently approved c-Met inhibitors and may justify its potent in vitro and in vivo activities. Therefore, the dual c-Met/ABL1 inhibitor HVS could not only be effective in slowing TNBC progression but also could prevent drug resistance. Detailed molecular and cellular mechanistic studies of oleocanthal and its bioisosteres indicate their potential for future use to control TNBC and other c-Met-dependent malignancies. This study was supported by NIH/NCI project 1R15CA167475-01.
Citation Format: Hassan Y. Ebrahim, Mohamed M. Mohyeldin, Abu Bakar Siddique, Mohamed R. Akl, Mostafa Ibrahim, Khalid A. El Sayed. Olive oil-based oleocanthal and bioisosteres as c-Met inhibitors for the control of triple negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 345.