Rational combination therapy for hepatocellular carcinoma with PARP1 and DNA-PK inhibitors

Abstract

Understanding differences in DNA double-strand break (DSB) repair between tumor and normal tissues would provide a rationale for developing DNA repair-targeted cancer therapy. Here, using knock-in mouse models for measuring the efficiency of two DSB repair pathways, homologous recombination (HR) and nonhomologous end-joining (NHEJ), we demonstrated that both pathways are up-regulated in hepatocellular carcinoma (HCC) compared with adjacent normal tissues due to altered expression of DNA repair factors, including PARP1 and DNA-PKcs. Surprisingly, inhibiting PARP1 with olaparib abrogated HR repair in HCC. Mechanistically, inhibiting PARP1 suppressed the clearance of nucleosomes at DNA damage sites by blocking the recruitment of ALC1 to DSB sites, thereby inhibiting RPA2 and RAD51 recruitment. Importantly, combining olaparib with NU7441, a DNA-PKcs inhibitor that blocks NHEJ in HCC, synergistically suppressed HCC growth in both mice and HCC patient-derived-xenograft models. Our results suggest the combined inhibition of both HR and NHEJ as a potential therapy for HCC.

Beyond DNA Repair: DNA-PKcs in Tumor Metastasis, Metabolism and Immunity

“…Synergistic combination therapy with DNA-PKcs inhibitors has also been investigated, especially with chemo- and radiotherapy [ 22 , 72 , 73 , 74 ]. More recently, combined PARP (Poly (ADP-ribose) polymerase)-targeted therapy and DNA-PKcs inhibitor have been demonstrated to synergistically inhibit tumor growth in both orthotopic mouse and patient-derived xenograft models of hepatocellular carcinoma [ 24 ]. Importantly, the combination regimen showed low toxicity, as no significant influence on liver, kidney, heart, and body weight was observed [ 24 ].…”

“…Reflecting this, numerous highly selective DNA-PKcs inhibitors such as NU7441, M3814, AZD7648, and NU5455 have been developed [ 15 , 16 , 22 , 23 ] and are being evaluated in clinical trials (NCT03770689, NCT04172532, NCT04533750). Although some promising preclinical and early-phase clinical results have been reported recently [ 15 , 22 , 24 , 25 , 26 ], the precise management of DNA-PKcs-based therapy for cancer patients remains a challenge due to the physiological role of DNA-PKcs and the lack of biomarkers that predict response to DNA-PKcs inhibitors. Therefore, the identification of biomarkers for DNA-PKcs inhibitor sensitivity is of great importance, not only for the development of precision therapeutic options based on DNA-PKcs inhibitor drugs but also for the mechanistic understanding of DNA-PKcs regulation.…”

Valproic Acid Regulates HR and Cell Cycle Through MUS81-pRPA2 Pathway in Response to Hydroxyurea

“…RPA2 is the key subunit of the homologous recombination (HR) repair mechanism induced by DNA replication fork stagnation (19,20). RPA2 comprises of multiple critical Ser/Thr residues that are phosphorylated sequentially in response to genotoxic stress (21).…”

Primary Founder Mutations in the PRKDC Gene Increase Tumor Mutation Load in Colorectal Cancer

“…Cells were subjected to 20 J/m 2 ultraviolet-C (UV-C) light irradiation, then were grown for 48 h either in the absence or presence of 2 μM NU7441 PRKDC inhibitor (iPRKDC) (also known as KU-57788) (Selleck Chemicals, Munich, Germany) [ 41 ]; or 20 μM KU-55933 (Selleck Chemicals) [ 42 ], inhibitor of ATM (iATM); or both compounds. The PRKDC inhibitor NU7441 is routinely used in the literature and is a well-characterized specific small molecular compound to counteract PRKDC action [ 43 , 44 , 45 ]. After drug treatment, the medium was changed to fresh medium without drugs, allowing recovery for an additional 48 h. Altogether, five rounds of treatments (UV with or without the drugs) were performed in combination with recovery periods.…”