Abstract 2586: PI3K/AKT signaling pathway is transcriptionally elevated in prexasertib-resistant TNBC PDX models
Authors: Ding Yan , Liu Jiangang , Calley John N. , Qian Hui-Rong , Iversen Philip W. , Ebert Philip J. , Beckmann Richard P. , Donoho Gregory P. , Martinez Ricardo , Wu Wenjuan , Lin Aimee Bence , Bowden Emma , Aggarwal Amit 
Published: August 2018

Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by poor clinical outcomes and limited treatment options. Transcriptional analysis has divided TNBC into different molecular subtypes (BL1, BL2, M and LAR) that were characterized with different signaling pathways and differed in response to similar neoadjuvant chemotherapies [1]. In a sporadic TNBC phase II study, prexasertib monotherapy showed modest single agent activity, which suggested that combination therapy is needed to maximize the benefit from prexasertib (LY2606368), a selective CHK1 inhibitor [2]. Here we leveraged a large cohort of TNBC patient-derived xenograft (PDX) models developed with nude mice to find biomarker/pathways/combination strategies related with prexasertib. Parametric Gene Set Enrichment Analysis (PGSEA) has been shown as a powerful sample-level analysis to generate enrichment scores for pathways [3]. First we confirmed that our collection of PDX models captured the heterogeneities of TNBC disease, with similar compositions of molecular subtypes as the TCGA dataset. The different molecular subtypes of PDX models also showed similar pathway changes as TNBC disease, such as increase of cell-cycle pathway in BL1-subtype, Glycolysis in BL2-subtype and ECM pathway in M-subtype. Molecular subtype analysis of a single-mouse (n=1) PDX trial evaluating antitumor activity of prexasertib showed that majority of M-subtype showed resistance to prexasertib and the other subtypes showed differential sensitivity. Within the BL1-subtype, the resistant models also showed high expression of stem-cell like features. Further PGSEA analysis based on KEGG signaling pathways revealed that the PI3K/mTOR pathway was transcriptionally elevated in resistant models, which was consistent with the additive effect of the combination therapy of prexasertib and PI3K/mTOR inhibitor (LY3023414) in this PDX trial. These data provide rationale for the development of combination therapy of prexasertib and PI3K/mTOR inhibitor for TNBC.
1. Lehmann, B.D., et al., Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One, 2016. 11(6): p. e0157368.
2. Karzai, F., et al., A phase II study of the cell cycle checkpoint kinases 1 and 2 (CHK1/2) inhibitor (LY2606368; prexasertib) in sporadic triple negative breast cancer (TNBC). Annals of Oncology, 2016. 27.
3. Kim, S.Y. and D.J. Volsky, PAGE: parametric analysis of gene set enrichment. BMC Bioinformatics, 2005. 6: p. 144.
Citation Format: Yan Ding, Jiangang Liu, John N. Calley, Hui-Rong Qian, Philip W. Iversen, Philip J. Ebert, Richard P. Beckmann, Gregory P. Donoho, Ricardo Martinez, Wenjuan Wu, Aimee Bence Lin, Emma Bowden, Amit Aggarwal. PI3K/AKT signaling pathway is transcriptionally elevated in prexasertib-resistant TNBC PDX models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2586.