Abstract PD3-02: Linking proliferative signal to DNA-damage signal in a tumor cell: A contextual synergy between the PI3K pathway and the DDR pathway in TNBC

Abstract

Abstract The phosphoinositide 3-kinase (PI3K) pathway signals not only for cell survival and proliferation in tumor cells but also controls DNA damage repair (DDR) and maintains HR (homologous recombination) steady-state the translational significance of which has been reported [Juvekar A. et al., 2012]. In breast cancers (BC), alterations of the PI3K pathway genes are both subtype-specific as well as contextual, and alterations of DDR pathway genes are one such contextual event occurring with the upregulation of the PI3K pathway. We hypothesized that there is contextual cooperation between the cellular signals of the PI3K and DDR pathways. We sought to identify the co-alterations of the PI3K and DDR pathway genes in our triple-negative BC (TNBC) patient cohort to (A) interrogate the contextuality of such alterations and (B) understand the mechanism of the contextual cooperation using an algorithmically chosen combination of pathway targeted drugs. We analyzed the somatic alterations profile of genes (FoundationOne, USA) in 264 BC patients (Avera Cancer Institute, SD, USA). We experimentally validated the cooperation between the pathways using alteration-guided targeted inhibitors; isoform-specific PI3K and PARP inhibitor(s) in the TNBC model, to demonstrate the efficacy of a combination of a node-specific targeted inhibitor(s) of the two pathways. The predominant type of mutation of genes in the PI3K pathway in our patients with TNBC was found in PTEN (Y68C, Y180*, loss, loss exons 1-5, and deletion exon1) and PIK3CA (amplification, E545K, H1047R). The other common mutation found was in TP53 (>80%) and somatic BRCA1/2 (~15%) genes. The interaction between the two pathways was evaluated, applying STRING10 to test the association at the highest 0.900 confidence views. The highest level of efficiency of drugs is demonstrated following the treatment of p110beta inhibitor (AZD 6482) in combination with PARP inhibitor (Olaparib/Talazoparib) plus DNA damaging agent (carboplatin) in BRCA-incompetent PTEN-null TNBC cells (SUM149) as compared to the efficiency of a combination of a PI3K pathway targeted inhibitor (of p110alpha) with a PARP inhibitor in BRCA-competent PTEN WT, but PIK3CA altered TNBC cells (BT20). The context-dependent synergy between the PI3K and DDR pathways in the TNBC model is comprehended at the levels of (1) load of DNA damage, (2) PARP activity, (3) of BRAC1/2 competency or HRD scores, and (4) mode of upregulation of PI3K pathway. We present an algorithm for a rational combination of the PI3K and the DDR pathway targeted drugs in TNBC. Citation Format: Nandini Dey, Jennifer Carlson Aske, Pradip De. Linking proliferative signal to DNA-damage signal in a tumor cell: A contextual synergy between the PI3K pathway and the DDR pathway in TNBC [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD3-02.