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.