Liu Wenjun, Barnette Annalise R, Andreansky Samita, Landgraf Ralf
Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida.
Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, Florida.
Mol Cancer Ther. 2016 Nov;15(11):2750-2757. doi: 10.1158/1535-7163.MCT-15-0932. Epub 2016 Jul 29.
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.
催化缺陷型ERBB3与受体酪氨酸激酶ERBB2强烈协同作用，其水平升高是乳腺癌不良疾病预后的总体危险因素。尽管它本身不是泛ERBB激酶抑制剂的靶点，但它会导致针对ERBB2的治疗方案产生耐药性。甾体内酯Withaferin A（WA）已通过多种作用方式确立了广泛的抗癌特性，并且在高浓度下对三阴性乳腺癌有效。我们发现ERBB2过表达确实使细胞对WA高度敏感。虽然高浓度WA处理会导致ERBB2下调，但这并不是低剂量时敏感性升高的原因。相反，WA靶向ERBB3放大ERBB2信号的能力。WA处理可消除ERBB3受体水平、ERBB3和ERBB2的组成型磷酸化以及通过AKT的信号传导。通过将ERBB2/ERBB3作为一个功能单元进行靶向，它在ERBB2导向抑制剂（如拉帕替尼）单独显示效力降低的情况下也有效。因此，WA或其衍生物可能是靶向ERBB2治疗药物的低毒性补充，特别是在ERBB3参与导致耐药或总体敏感性降低的情况下。分子癌症治疗；15(11)；2750 - 7。©2016美国癌症研究协会。
