Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, 21201, USA.
Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, 21201, USA; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, 21201, USA; Veterans Affairs Medical Center, Baltimore, MD, 20201, USA.
Cancer Lett. 2019 Jul 10;454:171-178. doi: 10.1016/j.canlet.2019.03.048. Epub 2019 Apr 4.
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 激酶内部串联重复（FLT3-ITD）发生在 20-25%的急性髓系白血病（AML）患者的跨膜结构域中，与不良治疗结果相关。已经开发了 FLT3 抑制剂，但由于耐药性的发展，其临床疗效有限，这突显了更好地了解 FLT3-ITD 的功能以及如何通过新的联合策略更有效地靶向它的必要性。多聚（ADP-核糖）聚合酶（PARP）抑制剂在因 BRCA 突变而导致同源重组（HR）受损的癌症中显示出疗效，但在包括 AML 在内的 BRCA 阳性癌症中，PARP 抑制剂的疗效尚未得到充分探索。最近的研究将 FLT3-ITD 信号抑制与许多 DNA 修复蛋白（包括参与 HR 的蛋白）的下调联系起来，新型联合 PARP 抑制剂在 AML 中诱导合成致死性。此外，PARP 抑制剂治疗也可能靶向 PARP 参与的高度易错的非同源末端连接（ALT NHEJ）DNA 修复途径，从而降低基因组不稳定性和治疗耐药性的发展。因此，PARP 抑制剂可能是与 FLT3 抑制剂联合治疗 FLT3-ITD AML 的有吸引力的治疗药物。
