Resistance to DNA repair inhibitors in cancer

Abstract

The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polh (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.Abbreviations ATR, Ataxia telangiectasia and Rad3 related gene; BRCA1, BRCA1 DNA repair-associated gene; BRCA2, BRCA2 DNA repair-associated gene; ctDNA, circulating tumour DNA; DDR, DNA damage response network; HR, homologous recombination; MMR, mismatch DNA repair; NAD+, nicotinamide adenine dinucleotide; PAR, poly-ADP-ribose; PARP1, poly-(ADP-ribose) polymerase 1 gene; PARPi, PARP inhibitor; POLQ, DNA polymerase theta gene, protein known as Polh; RS, replication stress; SWI/SNF, SWItch/sucrose non-fermentable chromatin remodelling complex; TMEJ, theta-mediated end joining; VEGF, vascular endothelial growth factor; WGR, protein domain containing tryptophan (W), glycine (G), arginine (R); WRN, Werner syndrome ATP-dependent helicase gene; ZnF, Zinc Finger protein domain.

The botanical drug PBI-05204, a supercritical CO2 extract of Nerium oleander, sensitizes alveolar and embryonal rhabdomyosarcoma to radiotherapy in vitro and in vivo

“…ATM contributes to radioresistance of several cancer cell types (Tribius et al, 2001;ZHOU et al, 2013;Bernardino-Sgherri et al, 2021;Cao et al, 2021;Zhang et al, 2022), resulting in an important pathway for DSB repair (Helleday, 2010), as also confirmed by García et al, 2022. Recently, a Phase I clinical trial investigating the radiosensitizing efficiency of M3541, a selective inhibitor of ATM, has closed unsuccessfully (Waqar et al, 2022), while another, assessing the safety and tolerability of the ATM inhibitor AZD1390 in combination to RT in patients with brain cancer is ongoing (NCT03423628). It has been largely shown that cancer cells can activate alternative survival pathways as a major mechanism of drug resistance and this also involves resistance to DNA repair inhibitors (Baxter et al, 2022). In this context, having available a drug capable of inhibiting the main pathways responsible for rhabdomyosarcomagenesis and DNA repair is certainly an advantage.…”

Multifaceted Nature of DNA Polymerase θ

“…The pharmacological effect of Pol θ inhibitors is consistent with the findings reported in studies using synthetic lethality. Defects of the HR pathway are the main sensitivity factors to therapy based on Pol θ inhibitors [ 58 , 109 ]. Such drugs are expected to combine very effectively with PARPi, a class of drugs for BRCA1/2-deficient tumors.…”

Clinical prospects of WRN inhibition as a treatment for MSI tumours

“…In this regard, it would be interesting to investigate whether MSI cancer cells with (TA) n repeat expansions have the potential to evolve resistance to WRN inhibition, by altering the length and/or sequences of the (TA) n repeat expansions, by inactivating MUS81-EME1 and/or SLX4 which may alleviate the DSB formation and chromosomal shattering, or by up-regulating genome stability processes, perhaps involving promiscuous DNA helicases that might compensate for WRN inhibition in this context. Importantly, reversion mutations of the underlying MMR defect would not confer resistance to WRN inhibition since the MSI phenotype would already be established 59 .…”