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

Georg E Winter1, Uwe Rix1, Scott M Carlson2

  • 1CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.

Nature Chemical Biology
|October 2, 2012
PubMed

Insights

A new drug combination of danusertib and bosutinib shows synergy against chronic myeloid leukemia (CML) with the T315I mutation. This therapy targets the c-Myc pathway, offering a novel approach for resistant CML cases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • The T315I gatekeeper mutation in BCR-ABL presents a significant challenge in treating chronic myeloid leukemia (CML).
  • Existing BCR-ABL inhibitors possess multiple targets, suggesting potential for synergistic therapeutic strategies.

Purpose of the Study:

  • To identify and elucidate the mechanism of synergistic drug combinations targeting BCR-ABL(T315I)-mutated CML cells.
  • To investigate the underlying molecular pathways affected by the synergistic drug combination.

Main Methods:

  • Systems-level analysis including phosphoproteomics, transcriptomics, and chemical proteomics.
  • Pharmacological validation of identified pathways and targets.
  • Testing drug combinations for synergistic effects on CML cells harboring the BCR-ABL(T315I) mutation.

Main Results:

  • A potent synergy was observed between danusertib and bosutinib, specifically in CML cells with the BCR-ABL(T315I) mutation.
  • Both drugs were found to target MAPK pathways downstream of BCR-ABL, leading to reduced c-Myc activity.
  • Pharmacological inhibition of MAPK pathways or Brd4 (which downregulates c-Myc) mimicked the effects of the drug combination.

Conclusions:

  • The combination of danusertib and bosutinib demonstrates a novel synergistic mechanism against BCR-ABL(T315I) CML.
  • This synergy is mediated by targeting the dependency of these CML cells on c-Myc through non-obvious off-target effects.
  • Systems-level data integration is crucial for uncovering complex drug interactions and therapeutic vulnerabilities.

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