Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors.

摘要: 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 this field PARP inhibitors (PARPi), which trigger synthetic lethality tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor HR and nonhomologous end joining, together PARPi should allow bypassing the genetic restriction for efficacy.Experimental Design: We characterized inhibition activity (olaparib) AsiDNA by monitoring foci formation damage. analyzed cell survival standalone combined 21 cells three nontumor cells. In 12 breast cancer (BC) lines, correlation sensitivity each drug transcriptome were statistically identify resistance pathways.Results: Molecular analyses demonstrate that olaparib respectively prevent recruitment XRCC1 RAD51/53BP1 enzymes damage sites. Combination both increases accumulation unrepaired resulting increase death all contrast, do not show nor lethality. Analysis multilevel omics data from BC highlighted different cell-cycle molecular profiles associated or olaparib, rationalizing treatment. Treatment synergy was also confirmed six other development.Conclusions: Our highlight therapeutic interest combining recapitulate independently their status. Clin Res; 23(4); 1001-11. ©2016 AACR.