Yeh Elizabeth S, Abt Melissa A, Hill Elizabeth G
Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Ave, BSB358, MSC509, Charleston, SC, 29425, USA,
Breast Cancer Res Treat. 2015 Jan;149(1):91-8. doi: 10.1007/s10549-014-3227-9. Epub 2014 Dec 17.
Breast cancer patients who are HER2-positive receive targeted inhibitors to HER2, including trastuzumab and lapatinib. While patients benefit from the use of HER2 inhibitors, many fail therapy and almost all patients become resistant to treatment, indicating a critical need to prevent treatment failure. Several recent studies indicate that activation of autophagy contributes to trastuzumab and lapatinib resistance and demonstrate that impairing autophagy in breast cancer cells is therapeutically beneficial. Moreover, autophagy is mechanistically linked through signaling crosstalk to apoptotic pathways, where activation of one process impacts the other. Therefore, understanding the molecular mechanisms that control these processes may uncover novel areas of therapeutic intervention to combat or prevent resistance in breast cancer. We previously characterized the protein kinase HUNK as a breast cancer-promoting factor in HER2/neu-induced mammary tumor models, in which HUNK supported the survival of HER2/neu-positive tumor cells, likely through the regulation of apoptosis. Because significant crosstalk exists between apoptotic and autophagy proteins, we now examine if HUNK is also able to regulate cell survival through modulation of autophagy using HER2 inhibitor sensitive and resistant breast cancer models. Furthermore, we investigate whether inhibiting HUNK impairs in vivo tumor growth that is initiated by HER2 inhibitor-resistant breast cancer cells. Our findings indicate that therapeutically targeting HUNK is a potential strategy for overcoming resistance and that resistant breast cancer cells maintain HUNK expression to drive tumorigenesis, an observation that is consistent with a pro-survival role for this kinase.
人表皮生长因子受体2（HER2）呈阳性的乳腺癌患者会接受针对HER2的靶向抑制剂治疗，包括曲妥珠单抗和拉帕替尼。虽然患者从使用HER2抑制剂中获益，但许多人治疗失败，几乎所有患者都会对治疗产生耐药性，这表明迫切需要预防治疗失败。最近的几项研究表明，自噬的激活会导致对曲妥珠单抗和拉帕替尼产生耐药性，并证明在乳腺癌细胞中抑制自噬具有治疗益处。此外，自噬通过信号串扰与凋亡途径在机制上相联系，其中一个过程的激活会影响另一个过程。因此，了解控制这些过程的分子机制可能会揭示新的治疗干预领域，以对抗或预防乳腺癌的耐药性。我们之前在HER2/neu诱导的乳腺肿瘤模型中将蛋白激酶HUNK鉴定为一种促进乳腺癌的因子，在该模型中，HUNK可能通过调节凋亡来支持HER2/neu阳性肿瘤细胞的存活。由于凋亡蛋白和自噬蛋白之间存在显著的串扰，我们现在使用对HER2抑制剂敏感和耐药的乳腺癌模型来研究HUNK是否也能够通过调节自噬来调节细胞存活。此外，我们研究抑制HUNK是否会损害由HER2抑制剂耐药的乳腺癌细胞引发的体内肿瘤生长。我们的研究结果表明，将HUNK作为治疗靶点是克服耐药性的一种潜在策略，并且耐药乳腺癌细胞维持HUNK表达以驱动肿瘤发生，这一观察结果与该激酶的促存活作用一致。
