Synergistic Antileukemic Activity And Molecular Mechanism Of Combined CUDC-907 And Mk-1775 In Acute Myeloid Leukemia

Acute myeloid leukemia(AML)is a heterogeneous hematological malignancy.AML is the most common type of acute leukemia,which is characterized by rapid proliferation and infiltration of immature myeloid precursor cells(or immature cells)into other tissues.In China,the annual incidence rate of AML is 1.62/100,000.AML accounts for 60% to 70% of adult acute leukemia cases.AML has high relapse rate,and once relapsed,it loses sensitivity to chemotherapy drugs(mainly cytarabine and daunorubicin or another anthracycline),leading to treatment failure.The overall fiveyear survival rate is only 26%.Therefore,there is an urgent need of better treatment to increase survival rate and improve quality of life of AML patients.When combined,phosphoinoside 3-kinase(PI3K)inhibitors and histone deacetylases(HDACs)inhibitors show synergistic antitumor activities against preclinical models of cancer.Based on this,the novel dual PI3 K and HDAC inhibitor CUDC-907(fimepiostat)was designed and synthesized.CUDC-907 shows promising preclinical activity against a variety of tumors including AML,and is currently in phase I and phase II clinical trials for the treatment of a variety of solid tumors.It is noteworthy that the US Food and Drug Administration(FDA)has granted CUDC-907 the fast track designation for treating adults with recurrent or diffuse large B-cell lymphoma.Previous studies show CUDC-907 can cause DNA damage.Therefore,we hypothesized that combining CUDC-907 with a cell cycle checkpoint inhibitor results in increased DNA damage and eventually cell death.The WEE1 kinase is a key protein in the DNA damage response(DDR)network.It regulates the G2/M cell cycle checkpoint via modulating the activity of cyclin dependent kinases(CDKs).MK-1775(adavosertib,also known as AZD-1775)is a selective WEE1 inhibitor,and shows promising antitumor activity in a variety of tumor models.In this thesis,CUDC-907 and MK-1775 were combined to induce more DNA damage and stronger antileukemic activity.We first demonstrated that the combination of CUDC-907 and MK-1775 has synergistic antileukemia activity against both AML cell lines and primary patient samples.Our mechanistic studies revealed that downregulation of CHK1,WEE1 and RNR,activation of CDK1,induction of DNA damage,and downregulation of c-Myc all play important roles in the synergistic antileukemic activity of CUDC-907 and MK-1775.This study supports the clinical evaluation of this promising combination therapy for the treatment of AML.