Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

摘要: Resistance to cell death is a hallmark of cancer and renders transformed cells resistant multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, key driver survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against panel cytogenetically primary human AML patient samples. We show PIK-75 transiently blocks Cdk7/9, leading transcriptional suppression MCL-1, rapid loss protein, alleviation its inhibition Bak. also targets p110α isoform PI3K, leads association between Bcl-xL simultaneous with Bak apoptosis cells. Concordantly, low expression confers resistance PIK-75–mediated killing. On other hand, induction by did not require BH3 proteins Bim, Bid, Bad, Noxa, or Puma. significantly reduced burden increased mice engrafted without inducing overt toxicity. Future efforts cotarget PI3K Cdk9 drugs such as are warranted.