Abstract 1077: Extra-virgin olive oil Met inhibitor oleocanthal-lapatinib: a novel synergistic combination for HER2-dependent breast malignancies

Abstract

Abstract Breast cancer (BC) is the most commonly diagnosed cancer in women, claiming the lives of hundreds of thousands of women each year. The Mediterranean diet is known to reduce BC and colon cancer incidence. Extra-virgin olive oil (EVOO) represents a main ingredient in this diet. The EVOO-derived (-)-oleocanthal was shown to target the Receptor tyrosine kinases (RTK) c-Met. Oleocanthal exerted potent in-vivo efficacy in an orthotopic athymic nude mouse breast cancer xenograft model much greater than its modest in-vitro potency. Dysregulation of RTKs, specifically EGFR/HER-2 pathways, correlates with poor prognosis and more aggressive breast cancer phenotypes. Dysregulation of hepatocyte growth factor (HGF) and its receptor c Met correlates with aggressive proliferation, invasive character, and pathological motility. c-Met amplification correlates with escape from the anticancer effects of EGFR/HER2 inhibitors and cetuximab. (-)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid from EVOO showed significant in vivo activity against invasive breast cancers through targeting HGF/Met axis. The Dual EGFR/HER-2 inhibitor lapatinib (LP) has already been in clinical practice for HER2-amplified breast cancer, which occasionally develops resistance through c-Met upregulation. Lapatinib’s therapeutic dose induced significant hepatotoxicity. The combined use of OC and LP was hypothesized not only for therapeutic synergy but also to notably reduce LP’s effective doses and therefore minimize its hepatotoxicity. Combined treatment of subeffective doses of lapatinib and OC caused significant in vitro and in vivo synergistic antiproliferative effects against the HER-2-dependent BT-474 and SKBR-3 BC cells. Interestingly, OC induced 4-fold lapatinib dose reduction index with improved potency. Protein microarray and Western blot analyses of OC-LP combination treatments synergistically reduced EGFR, HER-2, FAK, JAK1, MEK, and c-Met activation. These results propose OC use as dietary supplement to synergize the chemotherapeutic effects of LP, reduce its therapeutic dose to ¼ and therefore can minimize its morbidity. Combinatorial inhibition of c-Met-HER-2-EGFR is an effective strategy for the control of HER-2 positive breast cancer. This study was supported by NIH/NCI project 1R15CA167475-01. Citation Format: Abu Bakar Siddique, Hassan Y. Ebrahim, Mohamed R. Akl, Mohamed M. Mohyeldin, Khalid A. El Sayed. Extra-virgin olive oil Met inhibitor oleocanthal-lapatinib: a novel synergistic combination for HER2-dependent breast malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1077. doi:10.1158/1538-7445.AM2017-1077