Inhibition of tyrosine kinase BMX increases cell death in response to existing chemotherapeutic agents overcoming apoptotic resistance in cancer.

BMX tyrosine kinase has emerged as a novel drug target, the inhibition of which simultaneously decreases proliferative signaling and increases cell death. BMX expression is upregulated in numerous cancers and causes acquired resistance to chemotherapeutic drugs. In addition to being responsive to multiple signaling pathways involved in regulating proliferation, migration, and cell survival, BMX is also a direct and potent negative regulator of BAK that mediates apoptotic resistance. Knockdown of BMX in cancer cells dramatically potentiates BAK activation following DNA damage, rendering cells hypersensitive to killing by otherwise sub-lethal doses of drug irrespective of the mode of drug action. This study aimed to determine whether existing BMX inhibitors could increase cell killing when used in combination with chemotherapeutic agents. We now show this sensitization can be phenocopied using small molecules BMX inhibitors, confirming inhibition of regulators upstream of the apoptotic machinery is a novel strategy to modulate cell death and improve the efficacy of existing chemotherapeutic agents. Analysis of the binding of existing BMX inhibitors BMX-IN-1 and CHMFL-BMX-078 to the BMX kinase domain reveals these molecules' potential limitations, including the high cross-reactivity with other members of the TEC kinase family. This study serves as proof-of-principle for this therapeutic strategy but also highlights the urgent need for more specific molecules to inhibit BMX kinase activity. Created with BioRender.com.