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Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD.

ABSTRACT: Internal tandem duplications within the juxtamembrane domain of fms-like tyrosine kinase 3 (FLT3-ITD) occur in acute myeloid leukemia (AML) cells of 20-25% of patients and are associated with poor treatment outcomes. FLT3 inhibitors have been developed, but have had limited clinical efficacy due to development of resistance, highlighting the need for better understanding of the function of FLT3-ITD and how to target it more effectively using novel combination strategies. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in cancers with impaired homologous recombination (HR) due to BRCA mutations, but PARP inhibitor efficacy has not been fully explored in BRCA-proficient cancers, including AML. Recent research has connected inhibition of FLT3-ITD signaling to downregulation of numerous DNA repair proteins, including those involved in HR, and the novel combination with PARP inhibitors induces synthetic lethality in AML. Additionally, PARP inhibitor therapy may also target the highly error-prone alternative non-homologous end-joining (ALT NHEJ) DNA repair pathway in which PARP participates, thereby decreasing genomic instability and development of therapy resistance. Therefore, PARP inhibitors may be attractive therapeutic agents in combination with FLT3 inhibitors in FLT3-ITD AML.

SUBMITTER: Dellomo AJ

PROVIDER: S-EPMC6528833 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD.

Dellomo Anna J AJ Baer Maria R MR Rassool Feyruz V FV

Cancer letters 20190404

Internal tandem duplications within the juxtamembrane domain of fms-like tyrosine kinase 3 (FLT3-ITD) occur in acute myeloid leukemia (AML) cells of 20-25% of patients and are associated with poor treatment outcomes. FLT3 inhibitors have been developed, but have had limited clinical efficacy due to development of resistance, highlighting the need for better understanding of the function of FLT3-ITD and how to target it more effectively using novel combination strategies. Poly (ADP-ribose) polyme ...[more]

PMID: 30953707

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Project description:Acute myeloid leukemia (AML) is an aggressive hematologic malignancy which is cured in a minority of patients. A FLT3-internal tandem duplication (ITD) mutation, found in approximately a quarter of patients with de novo AML, imparts a particularly poor prognosis. Patients with FLT3-ITD AML often present with more aggressive disease and have a significantly higher propensity for relapse after remission. The therapeutic approach for these patients has traditionally included intensive induction chemotherapy, followed by consolidative chemotherapy or hematopoietic cell transplantation (HCT). In recent years, multiple small molecule inhibitors of the FLT3 tyrosine kinase have been studied preclinically and in clinical trials. The earlier generation of these agents, often non-specific and impacting a variety of tyrosine kinases, produced at best transient peripheral blood responses in early clinical trials. Additionally, the combination of FLT3 inhibitors with cytotoxic regimens has not, as of yet, demonstrated an improvement in overall survival. Nevertheless, multiple current trials, including those with sorafenib, lestaurtinib, and midostaurin, continue to study the combination of FLT3 inhibitors with standard chemotherapy. Factors such as sustained FLT3 inhibition, protein binding, pharmacokinetics, and the presence of elevated FLT3-ligand levels appear to significantly impact the potency of these agents in vivo. In recent years, the development of more specific and potent agents has generated hope that FLT3 inhibitors may play a more prominent role in the treatment of FLT3-ITD AML in the near future. Nevertheless, questions remain regarding the optimal timing and schedule for incorporation of FLT3 inhibitors. The suitability, type, and timing of allogeneic HCT in the therapeutic approach for these patients are also issues which require further study and definition. Recent retrospective data appears to support the efficacy of allogeneic HCT in first complete remission, possibly due to a graft versus leukemia effect. However, larger prospective studies are necessary to further elucidate the role of HCT and its potential combination with FLT3 inhibitor therapy. We are hopeful that current clinical investigation will lead to an optimization and improvement of outcomes for these patients.

Dataset Information

Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD.

Publications

Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD.

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