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Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML.

Abstract：

: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.

journal_name

Nat Chem Biol

journal_title

Nature chemical biology

authors

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

doi

10.1038/nchembio.1085

subject

Has Abstract

pub_date

2012-11-01 00:00:00

pages

905-912

issue

11

eissn

1552-4450

issn

1552-4469

journal_volume

8

pub_type

杂志文章

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