Withdrawn 25th Lorne Cancer Conference 2013

A double strike against leukaemia: Dual targeting of PI3K and Cdk9 rapidly and selectively induces apoptosis in human AML cells. (#195)

Daniel Thomas 1 , Jason Powell 1 , Francois Vergez 2 , David Segal 3 , Adele Baker 4 , Tracy Nero 5 , Michael W Parker 5 , Angel F Lopez 1 , Paul G Ekert 6 , Richard B Lock 7 , David CS Huang 6 , Susie K Nilsson 8 , Christian Recher 2 , Andrew H Wei 9 , Mark Guthridge 10
  1. Division of Human Immunology, SA Pathology, Adelaide, SA, Australia
  2. INSERM, Toulouse, France
  3. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
  4. Division of Blood Cancers, Australian Cente for Blood Diseases, Melbourne, VIC, Australia
  5. St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  6. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  7. Children's Cancer Institute Australia for Medical Research, Sydney, NSW, VIC
  8. CSIRO, Clayton, VIC, Australia
  9. Alfred Hospital , Melbourne, VIC, Australia
  10. Australian Centre for Blood Diseases, Melbourne, VIC, Australia

Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). In a screen for compounds down-regulating Mcl-1, we identified the kinase inhibitor, PIK-75, which demonstrates marked pro-apoptotic activity against AML stem and progenitor cells from a panel of 46 primary patient samples, including adverse cytogenetic risk, FLT3-ITD mutant and relapsed/refractory cases. PIK-75 induced a transient block in cyclin-dependent kinase 7 and 9 (Cdk7/9) activity leading to transcriptional suppression of MCL-1 and AML cell death. Importantly, concentrations of PIK-75 that promote apoptosis in primary human AML cells did not affect the survival of bone marrow progenitors from normal donors. In addition to inhibiting Cdk7/9, PIK-75 also targets the p110a isoform of phosphatidyl inositol 3-OH kinase (PI3K) and we show that dual inhibition of Cdk7/9 and PI3K is synergistic and necessary for optimal apoptosis of primary AML cells. PIK-75 killing was rapid (<6h), Bak-dependent and p53 independent. Importantly, PIK-75 treatment of mice engrafted with human AMLs significantly increased their median survival with no evidence of in vivo toxicity. Beyond AML, we also show that PIK-75 potently induces apoptosis in a panel of 16 cancer lines derived from multiple myeloma, brain and breast cancer. Our results identify a hitherto unrecognised alliance between PI3K and Cdk7/9 in promoting leukemic survival and show that dual inhibition of Cdk9 and PI3K by PIK-75 enhances apoptosis of AML cells. With limited efficacy demonstrated so far for PI3K and Cdk inhibitors in the clinic, future efforts to co-target PI3K:Akt and Cdk9:Mcl-1 with drugs such as PIK-75 in AML is warranted