AZD1775 sensitizes T cell acute lymphoblastic leukemia cells to cytarabine by promoting apoptosis over DNA repair.
While some children with acute lymphoblastic leukemia (ALL) have excellent prognoses, the prognosis for adults and children with T cell ALL is more guarded. Treatment for T-ALL is heavily dependent upon antimetabolite chemotherapeutics, including cytarabine. Targeted inhibition of WEE1 with AZD1775 has emerged as a strategy to sensitize cancer cells to cytarabine and other chemotherapeutics. We sought to determine if this strategy would be effective for T-ALL with clinically relevant anti-leukemia agents. We found that AZD1775 sensitizes T-ALL cells to several traditional anti-leukemia agents, acting synergistically with cytarabine by enhancing DNA damage and apoptosis. In addition to increased phosphorylation of H2AX at serine 139 (γH2AX), AZD1775 led to increased phosphorylation of H2AX at tyrosine 142, a signaling event associated with promotion of apoptosis over DNA repair. In a xenograft model of T-ALL, the addition of AZD1775 to cytarabine slowed leukemia progression and prolonged survival. Inhibition of WEE1 with AZD1775 sensitizes T-ALL to several anti-leukemia agents, particularly cytarabine and that mechanistically, AZD1775 promotes apoptosis over DNA repair in cells treated with cytarabine. These data support the development of clinical trials including AZD1775 in combination with conventional chemotherapy for acute leukemia.
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.|University of Nebraska Medical Center, Omaha, Nebraska, USA.
James B
JB
Ford
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
Dmitry
D
Baturin
Medical Scientist Training Program, University of Colorado School of Medicine, Aurora, Colorado, USA.
Tamara M
TM
Burleson
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
Annemie A
AA
Van Linden
Department of Pediatrics, University of Southern California, Los Angeles, California, USA.
Yong-Mi
YM
Kim
Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
Christopher C
CC
Porter
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D003561:Cytarabine / Q000494:pharmacology; D004260:DNA Repair / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011744:Pyrimidinones; D023041:Xenograft Model Antitumor Assays
D011720:Pyrazoles; D011743:Pyrimidines; D011744:Pyrimidinones; D003561:Cytarabine; C549567:adavosertib
DNA damage; Wee1; experimental therapeutics; kinase; leukemia