Abstract IA08: PI3K- and PARP-inhibitors for the treatment of women cancers.

Abstract

Abstract Amplification of PIK3CA is highly prevalent in ovarian cancer and isoform-specific and pan-PI3K inhibitors have entered clinical trials. However, identifying tumor subtypes and biological mechanisms that predict for response to PI3K inhibitors as single agents or in combination has been a challenge. We previously reported that combining a phophoinositide 3-kinase (PI3K) inhibitor with a poly ADP ribose polymerase (PARP)-inhibitor enhanced DNA damage and cell death in breast cancers that have genetic aberrations in BRCA1 and TP53. We now show that the enhanced DNA damage induced by PI3K inhibitors in this mutational background is a consequence of impaired production of deoxynucleotides needed for DNA synthesis and DNA repair. Inhibition of PI3K causes a reduction in all four deoxynucleotide triphosphates (dATP, dTTP, dGTP and dCTP), while inhibition of AKT is less effective than inhibition of PI3K in suppressing nucleotide synthesis and inducing DNA damage. Carbon flux studies reveal that PI3K-inhibition disproportionately affects the non-oxidative pentose phosphate pathway (non-ox PPP) that delivers ribose-5-posphate required for base ribosylation. In vivo in a mouse model of BRCA1-linked triple-negative breast cancer combined PI3K- and PARP-inhibition was superior to either agent alone to induce durable remissions of established tumors. Our data indicate that PI3K inhibitors induce DNA damage in tumors that have defects in DNA damage repair pathways and that they do so by impairing the production of Ribose-5-phosphate and amino acids needed for deoxynucleotide synthesis. An ongoing phase I/II study (NCT01623349, PI: Matulonis) examines the safety and toxicity of a PI3K/Parp-inhibitor combination in ovarian and breast cancer. Citation Format: Gerburg M. Wulf, Ashish Juvekar, Lewis C. Cantley, Ursula A. Matulonis. PI3K- and PARP-inhibitors for the treatment of women cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA08.