Lu Hezhe, Liu Shujing, Zhang Gao, Zhu Yueyao, Frederick Dennie T, Hu Yi, Zhong Wenqun, Randell Sergio, Sadek Norah, Zhang Wei, Chen Gang, Cheng Chaoran, Zeng Jingwen, Wu Lawrence W, Zhang Jie, Liu Xiaoming, Xu Wei, Krepler Clemens, Sproesser Katrin, Xiao Min, Miao Benchun, Liu Jianglan, Song Claire D, Liu Jephrey Y, Karakousis Giorgos C, Schuchter Lynn M, Lu Yiling, Mills Gordon, Cong Yusheng, Chernoff Jonathan, Guo Jun, Boland Genevieve M, Sullivan Ryan J, Wei Zhi, Field Jeffrey, Amaravadi Ravi K, Flaherty Keith T, Herlyn Meenhard, Xu Xiaowei, Guo Wei
Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Nature. 2017 Oct 5;550(7674):133-136. doi: 10.1038/nature24040. Epub 2017 Sep 27.
Targeted BRAF inhibition (BRAFi) and combined BRAF and MEK inhibition (BRAFi and MEKi) therapies have markedly improved the clinical outcomes of patients with metastatic melanoma. Unfortunately, the efficacy of these treatments is often countered by the acquisition of drug resistance. Here we investigated the molecular mechanisms that underlie acquired resistance to BRAFi and to the combined therapy. Consistent with previous studies, we show that resistance to BRAFi is mediated by ERK pathway reactivation. Resistance to the combined therapy, however, is mediated by mechanisms independent of reactivation of ERK in many resistant cell lines and clinical samples. p21-activated kinases (PAKs) become activated in cells with acquired drug resistance and have a pivotal role in mediating resistance. Our screening, using a reverse-phase protein array, revealed distinct mechanisms by which PAKs mediate resistance to BRAFi and the combined therapy. In BRAFi-resistant cells, PAKs phosphorylate CRAF and MEK to reactivate ERK. In cells that are resistant to the combined therapy, PAKs regulate JNK and β-catenin phosphorylation and mTOR pathway activation, and inhibit apoptosis, thereby bypassing ERK. Together, our results provide insights into the molecular mechanisms underlying acquired drug resistance to current targeted therapies, and may help to direct novel drug development efforts to overcome acquired drug resistance.
靶向 BRAF 抑制（BRAFi）以及 BRAF 和 MEK 联合抑制（BRAFi 和 MEKi）疗法显著改善了转移性黑色素瘤患者的临床结局。不幸的是，这些治疗的疗效常常因获得性耐药而受到影响。在此，我们研究了对 BRAFi 和联合疗法产生获得性耐药的分子机制。与先前的研究一致，我们发现对 BRAFi 的耐药是由 ERK 通路重新激活介导的。然而，在许多耐药细胞系和临床样本中，对联合疗法的耐药是由独立于 ERK 重新激活的机制介导的。p21 激活激酶（PAKs）在获得性耐药的细胞中被激活，并在介导耐药中起关键作用。我们使用反相蛋白质阵列进行的筛选揭示了 PAKs 介导对 BRAFi 和联合疗法耐药的不同机制。在 BRAFi 耐药细胞中，PAKs 磷酸化 CRAF 和 MEK 以重新激活 ERK。在对联合疗法耐药的细胞中，PAKs 调节 JNK 和 β-连环蛋白磷酸化以及 mTOR 通路激活，并抑制细胞凋亡，从而绕过 ERK。总之，我们的结果为当前靶向疗法获得性耐药的分子机制提供了见解，并可能有助于指导克服获得性耐药的新型药物开发工作。
