Abstract 663: The comparative efficacy of the PARP inhibitors AG14361, ABT888 and AZD2281 in the treatment of triple negative and BRCA1 breast cancer

Abstract

Introduction: Most preclinical studies have used “in vitro” animal cell lines, “in vivo” allografts and/or gene knockdowns to predict the clinical efficacy of PARP1 and PARP1 & 2 inhibitors in the treatment of human breast cancer. It has been shown however that “in vitro” experiments with human breast cancer cell lines are more useful in predicting the clinical performance of cancer drugs than these other methods. In this study, the PARP1 inhibitor AG14361 and the PARP1 & 2 inhibitors AZD2281 and ABT888 were tested against a panel of 25 human breast cancer cell lines. Methods: The MTT assay was used to determine the IC50 inhibitory effect of the PARP inhibitors against the human breast cancer cell lines over a 72 hour period with each experiment being replicated at least 10 times. The MTT assay was validated for each cell line using direct counting via hemacytometer & trypan blue staining. Human to mouse xenografts were then challenged by PARP inhibitors. The IC50 results were then correlated with the PARP activity of each cell line. Results: The PARP1 inhibitor AG14361 was 5 and 8 fold more effective in inhibiting human breast cancer growth than ABT888 and AZD2281 respectively. The average IC50 values for AG14361, ABT888 and AZD2281 against BRCA1-/- human breast cancer cell lines were 20, 120, and 190 micromolar respectively. The average IC50 values for non-BRCA1 triple negative breast cancer were 24, 110 and 165 micromolar respectively. ANOVA analysis sustained the null hypothesis between BRCA1-/- breast cancer and non-BRCA1 triple negative breast cancer. Xenograft studies mirrored the “in vitro results”. These IC50 values are significantly higher than previously published preclinical data that utilized BRCA1 -/- animal cell lines and human BRCA1 gene knockdowns. This suggests that BRCA1 animal cell lines are more sensitive to PARP1 inhibitors and that human BRCA1 -/- gene knockdowns may be fundamentally different from naturally derived BRCA1-/- breast cancer cell lines. Conclusion: The PARP1 inhibitor was more effective than the PARP1 & 2 inhibitors in inhibiting breast cancer growth. Non-BRCA1 triple negative breast cancers were at least as sensitive to PARP inhibition as BRCA1 breast cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 663.