Danusertib and bosutinib have synergistic activity in imatinib-resistant CML cells.

  • Major finding: Danusertib and bosutinib have synergistic activity in imatinib-resistant CML cells.

  • Mechanism: Synergy between these BCR-ABL inhibitors is due to off-target effects on MAPK signaling and MYC.

  • Impact: This approach identifies targets for CML treatment and may be generalizable to other drug interactions.

Imatinib can elicit complete remissions in the majority of patients with chronic myelogenous leukemia (CML), but some patients develop resistance. Second-generation BCR–ABL kinase inhibitors have been developed that circumvent many resistance mechanisms, but none of them are effective against the BCR–ABL threonine-315 (T315) gatekeeper mutation. Winter and colleagues hypothesized that BCR–ABL kinase inhibitors that are inactive against T315-mutant CML cells might be effective in combination due to cooperation between unappreciated off-target effects. A strong synergistic effect was observed when danusertib and bosutinib were combined that was not observed in a BCR–ABL wild-type background or with any other inhibitor combinations. To decipher the mechanistic basis for this synergy, each kinase inhibitor was immobilized on sepharose beads to allow identification of interacting proteins through affinity purification and mass spectrometry. Interestingly, multiple kinases involved in MAPK signaling bound either danusertib or bosutinib but not the other inhibitors, suggesting that these drugs might cooperate to inhibit the MAPK pathway. Consistent with this possibility, combined use of an ERK inhibitor and a MEK inhibitor recapitulated the effect of danusertib and bosutinib on T315-mutant CML cells. Transcriptional analysis showed that the group of genes specifically downregulated by the combination of danusertib and bosutinib was enriched for target genes of MYC. Because one effect of MAPK signaling can be stabilization of MYC through serine-62 (S62) phosphorylation, the authors analyzed lysates of T315-mutant CML cells treated with danusertib and bosutinib and found that the drug combination decreased MYC S62 phosphorylation. Furthermore, JQ1, a tool compound that downregulates MYC, mimicked the effects of danusertib and bosutinib on T315-mutant CML cell viability. This study thus uncovers exploitable dependencies of imatinib-resistant CML and provides a systems-based framework for identifying the mechanisms of action of one or more drugs.

Winter GE, Rix U, Carlson SM, Gleixner KV, Grebien F, Gridling M, et al. Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML. Nat Chem Biol 2012 Sept 30 [Epub ahead of print].