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posted on 2023-03-31, 20:01 authored by Wael Jdey, Sylvain Thierry, Christophe Russo, Flavien Devun, Muthana Al Abo, Patricia Noguiez-Hellin, Jian-Sheng Sun, Emmanuel Barillot, Andrei Zinovyev, Inna Kuperstein, Yves Pommier, Marie Dutreix Supplementary figure S3. Estimation and functions of genes uniquely correlated with sensitivity to AsiDNA or olaparib. (A) Number of non-overlapping genes correlated with survival to AsiDNA and Ola. Relationship between the number of non-overlapping genes and the p-value from LOO Spearman correlation analysis of expression data from BC cell lines. (B) Atlas of Cancer Signaling Network (ACSN) global map. (C, D) Coverage of ACSN map with unique genes correlated with survival to AsiDNA or Ola in BC cell lines. Distribution of non-overlapping genes robustly correlated with survival to AsiDNA (C) or Ola (D). Red - Positive correlation with survival to treatment; Green - Negative correlation with survival to treatment. Functional modules as WNT-canonical, Cell-matrix adhesion, Cell polarity, MOMP are implicated in survival to both treatments, but regulated in an opposite manner.
Funding
SIRIC-Curie
Centre National de la Recherche Scientifique
Institut National de la Santé Et de la Recherche Médicale
CIFFRE-ANRT
Institut National du Cancer
History
ARTICLE ABSTRACT
Purpose: Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are PARP inhibitors (PARPi), which trigger synthetic lethality in tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and nonhomologous end joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy.Experimental Design: We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the cell survival to standalone and combined treatments of 21 tumor cells and three nontumor cells. In 12 breast cancer (BC) cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways.Results: Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of cell death in all tumor cells. In contrast, nontumor cells do not show an increase of DNA damage nor lethality. Analysis of multilevel omics data from BC cells highlighted different DNA repair and cell-cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with six other PARPi in development.Conclusions: Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status. Clin Cancer Res; 23(4); 1001–11. ©2016 AACR.
