Suppression of homology-dependent DNA double-strand break repair induces PARP inhibitor sensitivity inVHL-deficient human renal cell carcinoma

Abstract

The von Hippel-Lindau (VHL) tumor suppressor gene is inactivated in the vast majority of human clear cell renal carcinomas. The pathogenesis of VHL loss is currently best understood to occur through stabilization of the hypoxia-inducible factors, activation of hypoxia-induced signaling pathways, and transcriptional reprogramming towards a pro-angiogenic and pro-growth state. However, hypoxia also drives other pro-tumorigenic processes, including the development of genomic instability via down-regulation of DNA repair gene expression. Here, we find that DNA repair genes involved in double-strand break repair by homologous recombination (HR) and in mismatch repair, which are down-regulated by hypoxic stress, are decreased in VHL-deficient renal cancer cells relative to wild type VHL-complemented cells. Functionally, this gene repression is associated with impaired DNA double-strand break repair in VHL-deficient cells, as determined by the persistence of ionizing radiation-induced DNA double-strand breaks and reduced repair activity in a homology-dependent plasmid reactivation assay. Furthermore, VHL deficiency conferred increased sensitivity to PARP inhibitors, analogous to the synthetic lethality observed between hypoxia and these agents. Finally, we discovered a correlation between VHL inactivation and reduced HR gene expression in a large panel of human renal carcinoma samples. Together, our data elucidate a novel connection between VHL-deficient renal carcinoma and hypoxia-induced down-regulation of DNA repair, and identify potential opportunities for targeting DNA repair defects in human renal cell carcinoma.

DNA damage repair pathway alterations in metastatic clear cell renal cell carcinoma and implications on systemic therapy

“…This includes Poly (ADP-ribose) polymerase (PARP) inhibitors for which synthetic lethality in a DDR-impaired state has been proposed in preclinical RCC models. 31 Our study has several limitations. All patients in this retrospective cohort were treated at a single center, and as mentioned sample size limits our ability to correct for other factors and explores the significance of individual genes.…”

Prevalence of pathogenic variants in DNA damage response and repair genes in patients undergoing cancer risk assessment and reporting a personal history of early-onset renal cancer

“…Studies are in progress to assess cancer risk in different tissue types, and response to treatment due to a germline defect in DDRR genes 44 . A recent study showed that VHL inactivation in RC led to reduced expression of DDRR genes (such as BRCA1 and BRCA2 ), and thereby increased sensitivity to PARP inhibitors 45 . These results indicate that RC tumors with DDRR gene vulnerabilities may be responsive to PARP or other DDRR gene inhibitors under development.…”

Investigation of the role of VHL-HIF signaling in DNA repair and apoptosis in zebrafish

“…Similarly, Scanlon et al demonstrated that there was an accumulation of DNA damage in VHL defective ccRCC cell lines compared to VHL complemented cells [8]. There was also downregulation of genes that regulate DSB repair and mismatch repair (MMR) in the ccRCC cells, that may explain the increase in the DNA damage seen.…”

“…There are a multitude of HIF independent functions of pVHL that could be potentially targeted for ccRCC treatment, although these are not as intensively investigated as HIF regulation. These include microtubule stabilization and maintenance of the primary cilium, regulation of the extracellular matrix formation, and control of cell senescence and apoptosis, transcriptional regulation [6] and DNA repair [7,8]. The mutations in pVHL that cause pheochromocytoma retain the ability to regulate HIF degradation, indicating that HIF independent roles of pVHL are important for tumorigenesis [9].…”