Martz Colin A, Ottina Kathleen A, Singleton Katherine R, Jasper Jeff S, Wardell Suzanne E, Peraza-Penton Ashley, Anderson Gray R, Winter Peter S, Wang Tim, Alley Holly M, Kwong Lawrence N, Cooper Zachary A, Tetzlaff Michael, Chen Pei-Ling, Rathmell Jeffrey C, Flaherty Keith T, Wargo Jennifer A, McDonnell Donald P, Sabatini David M, Wood Kris C
Department of Pharmacology and Cancer Biology, Duke University, 450 Research Drive, Durham, NC 27710, USA.
Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA.
Sci Signal. 2014 Dec 23;7(357):ra121. doi: 10.1126/scisignal.aaa1877.
Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts.
癌细胞可激活多种信号通路以逃避药物的细胞毒性作用。我们构建并筛选了一个带有条形码的通路激活突变互补DNA文库，以鉴定那些在13种临床相关的靶向治疗存在的情况下能提高癌细胞存活率的突变体。我们发现，RAS-MAPK（丝裂原活化蛋白激酶）、Notch1、PI3K（磷脂酰肌醇3-激酶）-mTOR（雷帕霉素作用靶点）和ER（雌激素受体）信号通路的激活通常会赋予对这类药物选择的抗性。Notch1通路的激活促进了小鼠体内连续传代的乳腺癌异种移植瘤对他莫昔芬（一种ER靶向治疗药物）产生获得性抗性，而用γ-分泌酶抑制剂处理小鼠以抑制Notch信号传导可恢复他莫昔芬敏感性。肿瘤组织中Notch1活性标志物与乳腺癌患者对他莫昔芬的抗性相关。同样，Notch1信号传导的激活促进了培养的BRAF（V600E）黑色素瘤细胞对MAPK抑制剂产生获得性抗性，并且在一部分黑色素瘤患者的肿瘤中Notch1通路标志物的丰度增加。因此，Notch1信号传导可能是某些耐药性乳腺癌和黑色素瘤的治疗靶点。此外，对MAPK抑制剂具有内在抗性的黑色素瘤细胞系中激活了多种抗性通路，同时抑制这些通路可协同诱导药物敏感性。这些数据说明了系统鉴定控制耐药性的信号通路的潜力，这可为多种癌症的临床策略和药物开发提供信息。这种方法也可用于推进其他疾病背景下的临床选择。
