Schwartz Harvey, Scroggins Brad, Zuehlke Abbey, Kijima Toshiki, Beebe Kristin, Mishra Alok, Neckers Len, Prince Thomas
Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD, 20892, USA.
Cell Stress Chaperones. 2015 Sep;20(5):729-41. doi: 10.1007/s12192-015-0604-1. Epub 2015 Jun 13.
The merging of knowledge from genomics, cellular signal transduction and molecular evolution is producing new paradigms of cancer analysis. Protein kinases have long been understood to initiate and promote malignant cell growth and targeting kinases to fight cancer has been a major strategy within the pharmaceutical industry for over two decades. Despite the initial success of kinase inhibitors (KIs), the ability of cancer to evolve resistance and reprogram oncogenic signaling networks has reduced the efficacy of kinase targeting. The molecular chaperone HSP90 physically supports global kinase function while also acting as an evolutionary capacitor. The Cancer Genome Atlas (TCGA) has compiled a trove of data indicating that a large percentage of tumors overexpress or possess mutant kinases that depend on the HSP90 molecular chaperone complex. Moreover, the overexpression or mutation of parallel activators of kinase activity (PAKA) increases the number of components that promote malignancy and indirectly associate with HSP90. Therefore, targeting HSP90 is predicted to complement kinase inhibitors by inhibiting oncogenic reprogramming and cancer evolution. Based on this hypothesis, consideration should be given by both the research and clinical communities towards combining kinase inhibitors and HSP90 inhibitors (H90Ins) in combating cancer. The purpose of this perspective is to reflect on the current understanding of HSP90 and kinase biology as well as promote the exploration of potential synergistic molecular therapy combinations through the utilization of The Cancer Genome Atlas.
基因组学、细胞信号转导和分子进化等领域知识的融合，正在催生癌症分析的新范式。长期以来，人们一直认为蛋白激酶会引发并促进恶性细胞生长，在过去二十多年里，将激酶作为抗癌靶点一直是制药行业的一项主要策略。尽管激酶抑制剂（KIs）最初取得了成功，但癌症产生耐药性以及重新编程致癌信号网络的能力，降低了激酶靶向治疗的效果。分子伴侣HSP90在物理上支持整体激酶功能，同时还充当进化电容器。癌症基因组图谱（TCGA）收集了大量数据，表明很大比例的肿瘤过度表达或拥有依赖HSP90分子伴侣复合物的突变激酶。此外，激酶活性平行激活剂（PAKA）的过度表达或突变会增加促进恶性肿瘤的成分数量，并间接与HSP90相关联。因此，预计靶向HSP90可通过抑制致癌重编程和癌症进化来补充激酶抑制剂。基于这一假设，研究界和临床界都应考虑将激酶抑制剂和HSP90抑制剂（H90Ins）联合用于抗癌。本文的目的是反思目前对HSP90和激酶生物学的理解，并通过利用癌症基因组图谱促进对潜在协同分子治疗组合的探索。
