ERBB2 overexpression establishes ERBB3-dependent hypersensitivity of breast cancer cells to withaferin A

Wenjun Liu, Annalise R. Barnette, Samita Andreansky, Ralf Landgraf

Research output: Contribution to journalArticle

3 Scopus citations

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 ofWAtreatment 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 byWAtreatment. 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.

Original languageEnglish (US)
Pages (from-to)2750-2757
Number of pages8
JournalMolecular Cancer Therapeutics
Volume15
Issue number11
DOIs
StatePublished - Nov 1 2016

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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