Targeting abnormal DNA double-strand break repair in tyrosine kinase inhibitor-resistant chronic myeloid leukemias

Abstract

Resistance to imatinib (IM) and other BCR-ABL1 tyrosine kinase inhibitors (TKI)s is an increasing problem in leukemias caused by expression of BCR-ABL1. Since chronic myeloid leukemia (CML) cell lines expressing BCR-ABL1 utilize an alternative non-homologous end-joining pathway (ALT NHEJ) to repair DNA double strand breaks (DSB)s, we asked whether this repair pathway is a novel therapeutic target in TKI-resistant disease. Notably, the steady state levels of two ALT NHEJ proteins, poly-(ADP-ribose) polymerase 1 (PARP1) and DNA ligase IIIα were increased in the BCR-ABL1-positive CML cell line K562 and, to a greater extent, in its imatinib resistant (IMR) derivative. Incubation of these cell lines with a combination of DNA ligase and PARP inhibitors inhibited ALT NHEJ and selectively decreased survival with the effect being greater in the IMR derivative. Similar results were obtained with TKI-resistant derivatives of two hematopoietic cell lines that had been engineered to stably express BCR-ABL1. Together our results show that the sensitivity of cell lines expressing BCR-ABL1 to the combination of DNA ligase and PARP inhibitors correlates with the steady state levels of PARP1 and DNA ligase IIIα, and ALT NHEJ activity. Importantly, analysis of clinical samples from CML patients confirmed that the expression levels of PARP1 and DNA ligase IIIα correlated with sensitivity to the DNA repair inhibitor combination. Thus, the expression levels of PARP1 and DNA ligase IIIα serve as biomarkers to identify a subgroup of CML patients who may be candidates for therapies that target the ALT NHEJ pathway when treatment with TKIs has failed.

Alternative NHEJ Pathway Components Are Therapeutic Targets in High-Risk Neuroblastoma

“…There is increasing evidence that deregulation of NHEJ is a pathogenic factor in a number of cancers, including breast cancer, chronic myelogenous leukemia (CML), and soft-tissue sarcomas (34)(35)(36)(37)(38). Our results provide new evidence that NHEJ is deregulated in neuroblastoma and provide explanation for the increased propensity of neuroblastoma tumors to harbor pathogenic segmental chromosomal alterations.…”

“…There is an immediate need to develop improved therapies for children with neuroblastoma refractory to current therapies. Targeting alt-NHEJ in select cancers is a promising therapeutic strategy for patients who fail conventional treatment modalities (36,37). The recent success of PARP1 inhibitors in clinical trials for select solid tumors has also given promise to alternative DNA repair mechanisms as cancer-specific therapeutics (43).…”

miR-22 suppresses DNA ligase III addiction in multiple myeloma

“…By comparing prognostic relevance of DNA ligases mRNA expression through whole gene expression data set analyses, we found that high LIG3 mRNA levels were significantly correlated to worse outcome in MM patients and increased during progression of disease and in relapsed patients. These findings, were consistent with the pivotal role played by DNA ligase III in Alt-NHEJ, an highly errorprone DNA repair pathway, which is strongly involved in the genomic instability, chromosome translocations, and drug resistance of different tumors, such as leukemia, lymphoma, neuroblastoma, and breast cancer [44][45][46][47]. In addition to its role on nuclear DNA repair, LIG3 gene encodes also the principal DNA ligase involved in mtDNA replication and repair, essential requisite to sustain mitochondrial contribute to cancer cell survival [48][49][50].…”

Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy

“…This strategy is supported by recent findings in artificially selected, therapy-resistant cell lines expressing high levels of PARP1 and Lig3a. 42,43 These cell lines were more sensitive to inhibition of either PARP1 or Lig3a alone or in combination with anti-estrogen therapy compared with control cells.…”