The Emerging Role of Poly (ADP-Ribose) Polymerase Inhibitors as Effective Therapeutic Agents in Renal Cell Carcinoma

Abstract

Renal cell carcinoma (RCC) is the sixth most common cancer in the US. However, no significant changes in management have occurred since the tyrosine kinase era until the recent breakthrough with checkpoint inhibitors. Therefore, the need for more therapeutic options is paramount. Our objective was to determine whether PARP inhibition represents a novel therapeutic option for RCC. We used publicly available COSMIC, GDC Data Portal, and cBioPortal databases to explore mutations in DNA repair genes in RCC tissues from the TCGA cohort. We treated a human normal renal epithelial cell line RPTEC/TERT1 and two human renal cancer cell lines ACHN and CAKI-2 with PARPi niraparib, olaparib, rucaparib, veliparib, and talazoparib. Cell survival, cell proliferation, clonogenic ability, and apoptosis were assessed. RCC xenografts in SCID mice were treated with PARPi to evaluate their efficacy in vivo. Data mining revealed that ~27-32% of RCC tissues contain mutations in homologous recombination genes. Niraparib and talazoparib were the most effective at reducing cell survival, proliferation, and clonogenic ability in vitro. Niraparib, talazoparib, and rucaparib were the most effective in reducing RCC xenograft growth in vivo. Agents such as PARPi that exploit mutations in DNA damage repair genes may be effective therapeutic options for RCC.

The germline mutational landscape of genitourinary cancers and its indication for prognosis and risk

“…For example, locally advanced or metastatic genitourinary cancer patients with BRCA1/2 mutations may be treated with poly ADP-ribose polymerase (PARP) inhibitors. Although it has long been known that PARP inhibitors were effective for prostate cancer with pathogenic or likely pathogenic BRCA1/2 mutations [ 46 , 47 ], it was not until recently that evidence started to emerge that PARP inhibitors were also effective in other genitourinary malignancies [ 47 – 51 ], except in renal cell carcinoma, since no evidence on the presence of BRCA1/2 mutations has been available in the cancer [ 52 ]. Similarly, locally advanced or metastatic cancer patients with germline mutations of MMR genes may be treated with immune checkpoint inhibitors such as PD-l inhibitors, as these cancers generally exhibit high tumor mutational burden and/or high microsatellite instability [ 53 ].…”

PARP inhibitors chemopotentiate and synergize with cisplatin to inhibit bladder cancer cell survival and tumor growth

“…We sought to determine the correlation between mutations in DDR pathway genes and BLCA patient survival. The list of DDR genes for which we sought to determine mutational status is from [28] and the percentage of mutations found in those genes in BLCA tissues from the TCGA cohort are listed in Table 1. We also report the death rates from BLCA in the TCGA cohort based on mutation rates for each gene, where available.…”

“…We used GDC Data Portal, COSMIC, and cBioPortal to analyze mutation rates in DNA repair genes [28] in BLCA patient tumors from the TCGA. The data revealed that ATM, ERCC2, BRCA2, ATR, and TP53 mutations are highly prevalent in BLCA tissues from the TCGA cohort (Table 1).…”

Roles of DNA damage repair and precise targeted therapy in renal cancer (Review)

“…As a PARPi, olaparib reverses drug resistance to sorafenib in liver cancer (90). A total of 27-32% of RCC tissue samples have mutations in HR genes, while PARPi agents (such as niraparib, talazoparib and rucaparib) that target DDR mutations may be effective treatment options for RCC (91). Due to increased PARP1 expression and decreased PARG levels, ccRCC is accompanied by increased levels of poly(ADPribose) (pADPr).…”