近期的《自然—化學生物學》報道了兩種針對致癌基因BCR-ABL的藥物的脫靶效應,，該效應的產(chǎn)生正好說明了這兩種藥物在誘導發(fā)生管家突變的白血病細胞的凋亡方面具有協(xié)同選擇的能力,。
致癌基因BCR-ABL的存在是白血病的特點之一,，而特定激酶抑制劑的使用能夠產(chǎn)生很好的臨床治療效果。在所謂的BCR-ABL管家殘留物上產(chǎn)生的BCR-ABL突變能讓癌細胞對現(xiàn)有的所有臨床藥物產(chǎn)生抗性,。因此,，針對發(fā)生突變的白血病研究出新治療方法并了解療效背后的生物學原理成為首要任務。
Giulio Superti-Furga等人證實,，danusertib和bosutinib這兩種BCR-ABL抑制藥物的結合能夠對發(fā)生陽性管家突變的白血病產(chǎn)生選擇性療效,，與這兩種藥物針對主要靶點BCR-ABL所產(chǎn)生的療效是相互獨立的,。研究人員將轉錄組學、磷酸化蛋白質組學與化學蛋白質組學三者相結合,，確認MAP激酶在生物學協(xié)同作用方面起到脫靶點的作用。他們同時還找到證據(jù)顯示,，處于MAP激酶下游位置的致癌基因c-MYC活性的變化作為收斂臨界點,，證明了這兩種藥物的結合活性。（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.
