Sci Signal：癌细胞产生耐药性的精细路径

  近日，刊登在国际杂志Science Signaling上的两篇研究论文中，来自美国杜克癌症研究所（Duke Cancer Institute）的研究人员通过研究揭示了促进特定癌细胞对致死性疗法产生耐药性的分子机制。
  文章中，通过绘制黑色素瘤、乳腺癌及骨髓纤维化癌细胞对特定药物产生耐药性的关键步骤，研究人员揭示了许多阻断癌细胞产生耐药性的关键靶点，对于后期开发有效应对癌症的疗法非常重要。研究者Kris Wood说道，目前抗癌疗法的临床耐药性是主要的问题所在，而当前解决该问题最符合逻辑的策略就是揭示肿瘤细胞产生耐药性的分子机理。
  研究者表示，我们开发了一种筛查技术，可以帮助我们快速有效地鉴别出产生耐药性的细胞路径，而利用这种关键路径我们就可以在实验室中研究如何抑制癌细胞产生耐药性。随后研究者对一系列细胞信号路径进行了广泛的观察调查，当这些信号路径激活时其就会引发癌细胞产生耐药，当然这种关键机制在临床上也是相关的。
  研究者Wood说道，更有意思的是，这种机制在所有上述三种癌症中是非常相似的，在乳腺癌和黑色素瘤中，研究者发现Notch-1通路是诱发癌细胞产生耐药性的潜在驱动子。而在骨髓纤维化疾病中，研究人员追踪了RAS信号分子下游的一对分离的信号通路，当其被激活后就会通过抑制癌细胞死亡来对当前的靶向药物疗法产生抗性。
  在第二篇研究论文中，研究者揭示，靶向作用RAS的信号路径或许可维持当前疗法的疗效。本研究或可帮助研究人员对病人进行分类来使其更加有效地对疗法产生反应，也将帮助开发出新型的药物联合疗法来阻断或者抑制癌细胞耐药性的产生。（转化医学网360zhyx.com）
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Systematic identification of signaling pathways with potential to confer anticancer drug resistance
Sci. Signal DOI: 10.1126/scisignal.aaa1877
Colin A. Martz1,*, Kathleen A. Ottina2,3,*, Katherine R. Singleton1,*, Jeff S. Jasper1, Suzanne E. Wardell1, Ashley Peraza-Penton1, Grace R. Anderson1, Peter S. Winter1, Tim Wang2,3,4, Holly M. Alley1, Lawrence N. Kwong5, Zachary A. Cooper5, Michael Tetzlaff5, Pei-Ling Chen5, Jeffrey C. Rathmell1, Keith T. Flaherty6, Jennifer A. Wargo5, Donald P. McDonnell1, David M. Sabatini2,3,4,†, and Kris C. Wood1,†
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 BRAFV600E 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.

RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis
Sci. Signal DOI: 10.1126/scisignal.2005301
Peter S. Winter1, Kristopher A. Sarosiek2,3, Kevin H. Lin1, Manja Meggendorfer4, Susanne Schnittger4, Anthony Letai2,3, and Kris C. Wood1,*
Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2V617F mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2V617F hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal–regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2V617F cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2)–associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2–like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co-occur with the JAK2V617F mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance.