近期的《自然—化学生物学》报道了两种针对致癌基因BCR-ABL的药物的脱靶效应，该效应的产生正好说明了这两种药物在诱导发生管家突变的白血病细胞的凋亡方面具有协同选择的能力。
致癌基因BCR-ABL的存在是白血病的特点之一，而特定激酶抑制剂的使用能够产生很好的临床治疗效果。在所谓的BCR-ABL管家残留物上产生的BCR-ABL突变能让癌细胞对现有的所有临床药物产生抗性。因此，针对发生突变的白血病研究出新治疗方法并了解疗效背后的生物学原理成为首要任务。
Giulio Superti-Furga等人证实，danusertib和bosutinib这两种BCR-ABL抑制药物的结合能够对发生阳性管家突变的白血病产生选择性疗效，与这两种药物针对主要靶点BCR-ABL所产生的疗效是相互独立的。研究人员将转录组学、磷酸化蛋白质组学与化学蛋白质组学三者相结合，确认MAP激酶在生物学协同作用方面起到脱靶点的作用。他们同时还找到证据显示，处于MAP激酶下游位置的致癌基因c-MYC活性的变化作为收敛临界点，证明了这两种药物的结合活性。（生物谷Bioon.com）
doi:10.1038/nchembio.1085
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Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML
Winter GE, Rix U, Carlson SM, Gleixner KV, Grebien F, Gridling M, Müller AC, Breitwieser FP, Bilban M, Colinge J, Valent P, Bennett KL, White FM, Superti-Furga G.
Occurrence of the BCR-ABL(T315I) gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL(T315I). To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL(T315I) CML cells on c-Myc through nonobvious off targets.
