Revealing Targeted Therapy for Human Cancer by Gene Module Maps. Homo sapiens

A major goal of cancer research is to match specific therapies to molecular targets in cancer. Genome-scale expression profiling has identified new subtypes of cancer based on consistent patterns of variation in gene expression, leading to improved prognostic predictions. However, how these new genetic subtypes of cancers should be treated is unknown. Here we show that a gene module map can guide the prospective identification of targeted therapies for genetic subtypes of cancer. By visualizing genome-scale gene expression in cancer as combinations of activated and deactivated functional modules, gene module maps can reveal specific functional pathways associated with each subtype that might be susceptible to targeted therapies. We show that in human breast cancers, activation of a poor-prognosis wound signature is strongly associated with induction of both a mitochondria gene module and a proteasome gene module. We found that 3-bromopyruvic acid, which inhibits glycolysis, selectively killed breast cells expressing the mitochondria and wound signatures. In addition, inhibition of proteasome activity by bortezomib, a drug approved for human use in multiple myeloma, abrogated wound signature expression and selectively killed breast cells expressing the wound signature. Thus, gene module maps may enable rapid translation of complex genomic signatures in human disease to targeted therapeutic strategies. Cell Line: Transduced construct Keywords: cell_type_comparison_design Overall design: Computed

癌症研究的核心目标之一，是实现特定疗法与癌症分子靶点的精准匹配。全基因组表达谱分析可基于基因表达的一致性变异模式，鉴定出新型癌症亚型，进而优化预后预测效能。然而，目前针对此类新型癌症遗传亚型的临床治疗方案仍未明确。本研究证实，基因模块图谱可指导癌症遗传亚型靶向治疗方案的前瞻性筛选与鉴定。通过将癌症的全基因组基因表达可视化表征为激活与失活功能模块的组合，基因模块图谱能够揭示与各癌症亚型相关的特定功能通路，而此类通路或可成为靶向治疗的潜在靶点。我们在人类乳腺癌样本中发现，预后不良的创伤特征的激活，与线粒体基因模块及蛋白酶体基因模块的诱导均存在显著相关性。研究显示，抑制糖酵解的3-溴丙酮酸可选择性杀伤携带线粒体基因模块与创伤特征的乳腺癌细胞。此外，硼替佐米——一种获批准用于多发性骨髓瘤的临床药物——通过抑制蛋白酶体活性，可消除创伤特征的表达，并选择性杀伤携带该创伤特征的乳腺癌细胞。综上，基因模块图谱可助力将人类疾病中的复杂基因组特征快速转化为靶向治疗策略。细胞系：转导构建体 关键词：细胞类型比较设计 整体设计：经计算