AsiDNA Treatment Induces Cumulative Antitumor Efficacy with a Low Probability of Acquired Resistance

Abstract

The Achilles heel of anticancer treatments is intrinsic or acquired resistance. Among many targeted therapies, the DNA repair inhibitors show limited efficacy due to rapid emergence of resistance. We examined evolution of cancer cells and tumors treated with AsiDNA, a new DNA repair inhibitor targeting all DNA break repair pathways. Effects of AsiDNA or Olaparib were analyzed in various cell lines. Frequency of AsiDNA- and olaparib-resistant clones was measured after 2 weeks of continuous treatment in KBM7 haploid cells. Cell survivals were also measured after one to six cycles of 1-week treatment and 1-week recovery in MDA-MB-231 and NCI-H446. Transcriptomes of cell populations recovering from cyclic treatments or mock treatment were compared. MDA-MB-231 xenografted models were treated with three cycles of AsiDNA to monitor the effects of treatment on tumor growth and transcriptional modifications. No resistant clones were selected after AsiDNA treatment (frequency < 3x10 −8 ) in treatment conditions that generate resistance to olaparib at a frequency of 7.2x10 −7 resistant clones per treated cell. Cyclic treatments promote cumulative sensitivity characterized by a higher mortality of cells having undergone previous treatment cycles. This sensitization was stable, and transcriptome analysis revealed a major gene downregulation with a specific overrepresentation of genes coding for targets of DNA-PK. Such changes were also detected in tumor models which showed impaired growth after cycles of AsiDNA treatment.

Evolution of tumor cells during AsiDNA treatment results in energy exhaustion, decrease in responsiveness to signal, and higher sensitivity to the drug

“…Actually, transcriptome analysis revealed a major change in gene expression with a large excess of genes down‐regulated in 3 independent “evolved” populations as compared to three independent “naïve” populations (Table ; access to raw data in GEO; GSE144023). A similar bias to repressed expression was observed in MDA‐MB‐231 tumors xenografts after three cycles of AsiDNA injection (Jdey et al, 2019). Strikingly, metabolic pathways were significantly deregulated in “evolved” cells as compared to “naïve” cells analyzed from cell culture or from tumors.…”

“…Indeed, poly(ADP‐ribose) polymerase (PARP) inhibitors, which have been tested for many years and have become a potential supplement to conventional chemotherapy, show increasing evidence of the appearance of resistance during treatment (Kim et al, 2017). In a recent work, it was reported that continuous or cyclic treatments with AsiDNA are much less prone to promote resistance emergence than regular DNA repair inhibitors (Herath et al, 2019; Jdey et al, 2019). In contrast, treated populations showed increased sensitivity to AsiDNA.…”

A Phase 1 dose-escalation study to evaluate safety, pharmacokinetics and pharmacodynamics of AsiDNA, a first-in-class DNA repair inhibitor, administered intravenously in patients with advanced solid tumours

“…γH2AX foci formation at DSB sites can recruit other DSB signalling and repair factors such as MDC1, 53BP1 and the MRN complex to the damage site. 25 Over the past several years, γH2AX expression has been established as a very sensitive surrogate biomarker of DSBs, mostly following radiation-less literature exists about CT. 8,18,[26][27][28] γH2AX expression remains phosphorylated if the DSBs are not repaired due to defects in the DSB repair machinery. Preclinical data in tumour showed that the AsiDNA-induced false damage signalling of γH2AX, phosphorylated Hsp90 and PARP activation significantly increased between 15 and 48 h after each AsiDNA administration and could be considered as early biomarkers of activity.…”

“…[13][14][15][16][17] AsiDNA was shown to induce cumulative antitumour activity with low probability of acquired resistance in preclinical models. 18 In the clinic, the drug was first investigated in 23 patients with skin metastases of melanoma in a Phase 1 dose-escalation study, 19 which evaluated the safety and pharmacokinetics (PK) of AsiDNA administered by SC (IT/ peri-tumoural) injections in combination with palliative RT. This first-in-human study of AsiDNA was conducted as a proof of concept of the ability of the drug to sensitise and improve RT response rate (estimated about 10% of complete response rate in melanoma) based on preclinical data showing an AsiDNAinduced radio-sensitisation in human melanoma xenografted models.…”

Preclinical Studies Comparing Efficacy and Toxicity of DNA Repair Inhibitors, Olaparib, and AsiDNA, in the Treatment of Carboplatin-Resistant Tumors

“…Moreover, it seems to delay the onset of resistance. Actually, whereas olaparib and carboplatin long-term treatments have a high risk of favoring growth of resistant clones in tumor, AsiDNA monotherapy, thanks to its original mechanism of action, seems to be less prone to such events (32). The combination of AsiDNA with carboplatin prevents the emergence of resistant cells in the chemosensitive BC227 cell line.…”