Department of Pharmacology, Emory University, Suite 5001, 1510 Clifton Rd., Atlanta, GA 30322. USA.
Curr Med Chem. 2014;21(4):501-10. doi: 10.2174/0929867320666131119155023.
Intrinsic or acquired resistance to the HER2-targeted therapy trastuzumab is a clinical concern in the treatment of patients with HER2-over-expressing metastatic breast cancers. We demonstrate here that multiple models of intrinsic and acquired resistance exhibit increased phosphorylation of p38 MAPK. Kinase inhibition of p38 rescued trastuzumab sensitivity in cells with acquired resistance. In addition, knockdown of p38 increased sensitivity to trastuzumab in an intrinsically resistant cell line. We previously reported that expression of growth differentiation factor 15 (GDF15) is increased in trastuzumab-resistant HER2-overexpressing breast cancer cells. In this study, we found that exogenous GDF15 or stable overexpression of GDF15 stimulated p38 phosphorylation in HER2-positive cells, suggesting a possible mechanism by which p38 is activated in resistant cells.GDF15 stable clones showed significantly increased invasiveness, which was rescued by p38 kinase inhibition, suggesting that p38 plays a role in the pro-invasive phenotype conferred by GDF15. Importantly, immunohistochemical analysis of a breast tumor tissue array indicated a significant (p=0.0053) correlation between HER2 and phosphorylated p38 specifically in GDF15-positive tissues. Our results suggest that p38 signaling drives trastuzumab resistance and invasiveness in HER2-overexpressing breast cancer. Upstream growth factor signals that have previously been implicated in trastuzumab resistance, such as GDF15, may contribute to the increased phosphorylation of p38 found in resistant cells.
曲妥珠单抗的内在或获得性耐药是 HER2 过表达转移性乳腺癌患者治疗中的一个临床关注点。我们在此证明，多种内在和获得性耐药模型均表现出 p38 MAPK 的磷酸化增加。p38 的激酶抑制可挽救获得性耐药细胞中曲妥珠单抗的敏感性。此外，p38 的敲低增加了内在耐药细胞系对曲妥珠单抗的敏感性。我们之前报道过，生长分化因子 15（GDF15）的表达在曲妥珠单抗耐药的 HER2 过表达乳腺癌细胞中增加。在这项研究中，我们发现外源性 GDF15 或 GDF15 的稳定过表达可刺激 HER2 阳性细胞中的 p38 磷酸化，这表明了 p38 在耐药细胞中被激活的可能机制。GDF15 稳定克隆显示出明显增加的侵袭性，p38 激酶抑制可挽救这种侵袭性，这表明 p38 在 GDF15 赋予的促侵袭表型中发挥作用。重要的是，对乳腺癌组织阵列的免疫组织化学分析表明，在 GDF15 阳性组织中，HER2 与磷酸化的 p38 之间存在显著相关性（p=0.0053）。我们的研究结果表明，p38 信号转导驱动了 HER2 过表达乳腺癌中曲妥珠单抗的耐药性和侵袭性。先前被认为与曲妥珠单抗耐药相关的上游生长因子信号，如 GDF15，可能导致耐药细胞中 p38 磷酸化的增加。
