Abstract
Dysregulation of epidermal growth factor receptor (EGFR)/human epidermal growth factor-2 (HER2) family is a hallmark of aggressive breast cancer. Small-molecule tyrosine kinase inhibitors are among the most effective cancer targeted treatments. (−)-Oleocanthal (OC) is a naturally occurring phenolic secoiridoid lead from extra-virgin olive oil with documented anti-cancer activities via targeting mesenchymal epithelial transition factor (c-Met). Dysregulation of c-Met promotes aggressiveness to breast cancer-targeted therapies. Lapatinib (LP) is an FDA-approved dual EGFR/HER2 inhibitor for HER2-amplified breast cancer. HER2-Positive tumor cells can escape targeted therapies like LP effects by overexpressing c-Met. Combined OC-LP treatment is hypothesized to be mechanistically synergistic against HER2-overexpressing breast cancer. Combined sub-effective treatments of OC-LP resulted in synergistic anti-proliferative effects against the HER2-positive BT-474 and SK-BR-3 breast cancer cell lines, compared to OC or LP monotherapy. Antibody array and Western blot analysis showed that combined OC-LP treatment significantly inhibited EGFR, HER2, and c-Met receptor activation, as well as multiple downstream signaling proteins, compared to individual OC or LP treatment. OC-LP Combination significantly inhibited invasion and migration of breast cancer cells through reduced activation of focal adhesion kinase (FAK) and paxillin. Combined treatment of OC-10 mg/kg with LP-12.5 mg/kg suppressed more than 90% of BT-474 tumor cells growth in a nude mouse xenograft model, compared to individual OC or LP treatment. Activated c-Met, EGFR, HER2, and protein kinase B (AKT) were significantly suppressed in combination-treated mice tumors, compared to OC or LP monotherapy. This study reveals the OC future potential as combination therapy to sensitize HER2-overexpressing breast cancers and significantly reduce required doses of targeted HER family therapeutics.
Highlights
The epidermal growth factor (ErbB, HER) family consists of four transmembrane receptor tyrosine kinases (RTKs); HER1 to HER4 [1]
Monotherapy of OC or LP treatments showed a dose-dependent inhibition of growth of BT-474 and SK-BR-3 cells, with IC50 values of 25.1 μM, 27.3 μM, 123.0 nM and
To assess the effect of combined OC and LP treatments, BT-474 and SK-BR-3 breast cancer (BC) cells treated with sub-μM doses of OC at 12 μM or 15 μM, respectively (Figure 2A,B)
Summary
The epidermal growth factor (ErbB, HER) family consists of four transmembrane receptor tyrosine kinases (RTKs); HER1 to HER4 [1]. Their dysregulations are strongly implicated in the pathogenesis of various human malignancies, associated with poor prognostic outcomes, aggressive phenotype profile, and poor disease outcomes, including reduced overall survival [2,3,4,5]. One of the clinically available HER2-targeted therapies is lapatinib (LP), an orally active small-molecule dual tyrosine kinase inhibitor (TKI) of epidermal growth factor receptor (EGFR) and HER2 kinases [8,9]. Despite success as HER2-targeted therapy, limitations to LP treatment monotherapy involved the emergence of both primary and acquired resistance among HER2-positive BC patients and multiple off-target side effects [12,13,14]
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