Off-target synergy for kinase inhibitors against drug resistant CML

The off-target activity of two drugs that target an oncogene, called BCR-ABL, explains their synergistic and selective ability to induce cell death in gatekeeper mutated chronic myeloid leukemia (CML) cells, reports a paper published online this week in Nature Chemical Biology.

The presence of BCR-ABL oncogene is a hallmark for CML, and targeted kinase inhibitors, have yielded impressive clinical treatment results for patients. Mutation of BCR-ABL at the so-called gatekeeper residue of BCR-ABL renders these cancers resistant to all drugs currently approved for clinical use. Identifying new strategies to treat CML with these mutations and understanding the biology underlying their effectiveness is thus a priority.

Giulio Superti-Furga and colleagues report that the combination of two BCR-ABL inhibitor drugs, danusertib and bosutinib, is selectively effective against gatekeeper mutation-positive CML, independent of their activity against their primary target, BCR-ABL. The authors combine three approaches (transcriptomics, phosphoproteomics and chemoproteomics) to identify MAP kinases as the off-target hits responsible for the biological synergy. They also provide evidence that changes in the activity of the oncogene c-MYC, acting downstream of MAPKs, as the critical point of convergence that explains the activity of the drug combination.