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

• Published in: Cancer letters 2019-07, Vol.454, p.171-178
• Main Authors: Dellomo, Anna J., Baer, Maria R., Rassool, Feyruz V.
• Format: Article
• Language: English
• Subjects: Acute myeloid leukemia; Adenosine diphosphate; Animals; Cancer therapies; Chemical compounds; Chemotherapy; Clinical trials; Cytotoxicity; DNA repair; Drug dosages; FDA approval; FLT3 inhibitors; Flt3 protein; FLT3-ITD; fms-Like Tyrosine Kinase 3 - genetics; Genomic Instability; Homologous recombination; Homology; Humans; Inhibitors; Kidney cancer; Kinases; Laboratories; Lethality; Leukemia; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - genetics; Liver cancer; Lymphoma; Medical prognosis; Metastasis; Mutation; Myeloid leukemia; Non-homologous end joining; PARP inhibitors; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - administration & dosage; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteins; R&D; Research & development; Ribose; Success; Targeted cancer therapy; Tumors
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2019.03.048

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. •FLT3 inhibitors alone have lacked success in FLT3-ITD mutated AML.•FLT3 and PARP inhibitors together successfully induce synthetic lethality.•PARP inhibitors likely reduce genomic instability in AML reducing mutations.