The potential of the PARP-1 inhibitor, AGO14699, in human cancers defective in homologous recombination DNA repair

Abstract

The aims of this study were to undertake the first comprehensive in vitro, in vivo and clinical investigation into the effects of the PARP-1 inhibitor, AG014699, in human cancers defective in homologous recombination (HR) DNA double strand break (DSB) repair. HR deficient cells were 9-fold more sensitive to AG014699 than HR proficient cells (mean LC50 = 3.26 μM vs. 29.68; P < 0.0001), confirming the theory of synthetic lethality. BRCA1 methylated UACC3199 breast cancer cells were also sensitive to AG014699 with mean LC50 significantly lower than the HR proficient cells (7.6 μM vs. 29.68; P = 0.002). AG014699 inhibited PARP activity by > 95% and induced DNA DSBs in all 11 cell lines studied. Evidence of HR (by Rad51 foci) was observed only in cells with functional BRCA1/2. A prolonged schedule of AG014699 (10 mg/kg daily for five days of a seven-day cycle for six cycles) more effectively delayed the growth of BRCA2 mutated xenografts than a ten day AG014699 schedule (tumour growth delay (TGD) = 27.5 vs. 12.5 days; P = 0.02). AG014699 significantly delayed UACC3199 tumour growth compared to untreated controls (mean time to relative tumour volume 5 = 35.8 vs. 25.2 days; P = 0.05); confirming in vitro findings that BRCA1 methylated cancer cells are sensitive to PARP inhibition. Clinical trial data from 38 patients demonstrated that AG014699 is non-toxic and efficacious with a clinical benefit rate of 34%. Higher baseline PARP-1 activity was associated with response to AG014699. The major findings of these studies are: the confirmation of the selective cytotoxicity of PARP inhibitors in BRCA mutated cancers; the results in UACC3199 cells which suggest that cancers with other HR defects could benefit from single agent PARP inhibitors, and finally the concept that length of exposure to (not just degree of) PARP inhibition is important for single agent anti-tumour activity. Furthermore, these data have formed the basis for a major amendment to the clinical trial; the result of which is eagerly awaited.