FLT3 tyrosine kinase inhibitors synergize with BCL-2 inhibition to eliminate FLT3/ITD acute leukemia cells through BIM activation.

摘要: Tyrosine kinase inhibitors (TKIs) targeting FLT3 have shown activity but when used alone achieved limited success in clinical trials, suggesting the need for combination with other drugs. We investigated of TKIs (Gilteritinib or Sorafenib), Venetoclax, a BCL-2 selective inhibitor (BCL-2i), on FLT3/ITD leukemia cells. The TKI and BCL-2i synergistically reduced cell proliferation enhanced apoptosis/cell death lines primary AML samples. Venetoclax also re-sensitized TKI-resistant cells to Gilteritinib Sorafenib treatment, mediated through MAPK pathway inhibition. treatment dissociated BIM from MCL-1 increased binding BCL-2. Treatment drugs together resulted dissociation both MCL-1, an mediator BAX, leading apoptosis. These findings suggest that mitigates unintended pro-survival effects mainly decreased expression. This study provides evidence addition enhances effect therapy treatment.