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Figure 2. Rationale for combinatorial treatment of AML exhibiting mutational activation of PI3K/AKT signaling with inhibitors of DNA-PK and/or PI3K/AKT and DSB-inducing AML chemotherapeutics (i.e., anthracyclines and HMAs). (A) AML cells harboring mutations in KIT, FLT3, JAK2, ASXL1, or NRAS/KRAS frequently exhibit constitutive “oncogenic” signaling including activation of the PI3K/AKT signaling pathway. Standard therapies for AML patients consist of: (1) cytarabine/anthracycline (dauno-, ida-, or doxorubicin) chemotherapy; or (2) HMAs such as azacytidine, which induce DSBs. Emerging therapy-induced DSBs launch a DDR partly via DNA-PK- and/or ATM-dependent complementary enhancement of AKT downstream signaling, which promotes: (1) proliferation; (2) survival; (3) glucose metabolism; (4) DNA repair; and, ultimately (5) therapy resistance. (B) Simultaneous treatment with inhibitors of DDR or PI3K/AKT signaling in combination with an anthracycline/HMA abrogates AKT downstream signaling and DNA repair, leading to increased DNA damage, apoptosis of AML cells, and ultimately better therapy response and clinical outcome. ATM: Ataxia telangiectasia mutated; ATR: ATR serine/threonine kinase; DDR: DNA damage response; DSBs: double-strand brakes; FLT3: fms related receptor tyrosine kinase 3; HMAs: hypomethylating agents; KIT: KIT proto-oncogene-receptor tyrosine kinase.