Abstract
The catalytically deficient ERBB3 strongly synergizes with the receptor tyrosine kinase ERBB2, and elevated levels represent an overall risk factor for unfavorable disease outcomes in breast cancer. Although itself not a target of pan-ERBB kinase inhibitors, it contributes to resistance in ERBB2-targeted treatment regiments. The steroidal lactone Withaferin A (WA) has established broad anticancer properties through several modes of action and was shown to be effective against triple-negative breast cancers at elevated concentrations. We found that ERBB2 overexpression does render cells hypersensitive to WA. Although ERBB2 downregulation is one aspect of WA treatment at high concentrations, it is not causal for the elevated sensitivity at lower dosages. Instead, WA targets the ability of ERBB3 to amplify ERBB2 signaling. ERBB3 receptor levels, constitutive phosphorylation of both ERBB3 and ERBB2, as well as signaling through AKT are eliminated by WA treatment. By targeting ERBB2/ERBB3 as a functional unit, it is also effective in cases in which ERBB2-directed inhibitors, such as lapatinib, alone show reduced potency. Hence, WA or derivatives thereof may present a low toxicity addition to ERBB2-targeting therapeutics, especially in cases in which ERBB3 involvement is driving resistance or reduced overall sensitivity. Mol Cancer Ther; 15(11); 2750-7. ©2016 AACR.
Highlights
Overexpression of the receptor tyrosine kinase ERBB2 (ErbB2, HER2) occurs in various solid tumors but most prominently in breast cancer, with approximately one third of patients displaying high ERBB2 levels due to gene amplification
Our analysis demonstrates that ERBB2 overexpression confers Withaferin A (WA) hypersensitivity in a manner that is correlated to the cell's level of dependency on synergistic signaling by ERBB3 and ERBB2
Previous work had demonstrated that the triple-negative line MDA-MB-231 as well as the ERBB2-negative MCF7 line are sensitive to WA [18]
Summary
Overexpression of the receptor tyrosine kinase ERBB2 (ErbB2, HER2) occurs in various solid tumors but most prominently in breast cancer, with approximately one third of patients displaying high ERBB2 levels due to gene amplification. ERBB3, the most potent heterodimerization partner of ERBB2, has emerged as a critical factor in both the initial oncogenicity as well as the emergence of resistance to ERBB2-directed therapies [1]. Impaired in its own kinase activity [3], ERBB3 acts as an allosteric activator of its heterodimerization partners [4], and elevated levels of ERBB3 are correlated with progression of several solid tumors [5,6,7,8,9,10].
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