AML mutation-guided drugging of DNA repair

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Current treatments of acute myeloid leukemia (AML) clear the disease burden consisting mostly of leukemia progenitor cells (LPCs), but they usually fail to eradicate leukemia stem cells (LSCs). Altered DNA repair mechanisms may be responsible for survival of LSCs and/or LPCs under genotoxic stress. DNA double-strand breaks (DSBs), the most lethal DNA lesions, are usually repaired by BRCA -mediated homologous recombination (HR) repair at the replication forks. BRCA-HR repair involves several proteins such as BRCA1, BRCA2, RAD54 and RAD51. An alternative HR pathway depends on RAD52-RAD51 (RAD52-HR). PARP1-mediated base excision repair (BER) and PARP1-dependent non-homologous end-joining (P-NHEJ) serve as back-ups/alternative mechanisms to prevent and/or repair DSBs. Cancer-specific defects in DNA repair create the opportunity to employ a phenomenon called synthetic lethality, e.g. elimination of BRCA1/2-mutated cancer cells by PARP1 inhibitor (PARP1i). Since inactivating mutations in BRCA-HR pathway are rare in AMLs, we obtained preliminary data suggesting that BRCA deficiency and BRCA proficiency on individual AMLs can be predicted by a comprehensive Gene Mutation Analysis (GMA) of AML-inducing genetic aberrations. This approach will be tested in Aim #1. BRCA-deficient AML LSCs/LPCs should be prone to PARP1i-induced synthetic lethality. However, therapeutic effect of PARP1i in BRCA1/2-deficient cells may be reduced by alternative RAD52-HR, which can protect, at least partially, BRCA-deficient PARP1i-treated cells from lethal effect of DSBs. Therefore, in Aim #2 we propose that combination of PARP1i+RAD52i may induce more effective synthetic lethality in BRCA deficient LSCs/LPCs. We will also develop drug-grade RAD52i. On the other hand, BRCA-proficient AML cells should be sensitive to the inhibitors of BRCA- HR pathway combined with PARP1i. Preliminary data suggest that RAD54 may be a valid target to induce BRCA-deficiency in BRCA-proficient cells. In Aim #3 we will examine if targeting RAD54 sensitizes BRCA-proficient AMLs to PARP1i - mediated synthetic lethality. We expect that personalized medicine-guided synthetic lethality combining drugs targeting DNA repair may be designed to eliminate AML LSCs/LPCs in individual patients.