Abstract 676A: Overcoming PARP inhibitor resistance with molecularly guided rational combinations in triple-negative breast cancer patient-derived xenograft models
Authors: Pico Christian X. Cruz , Evans Kurt W. , Chen Ken , Zheng Xiaofeng , Akcakanat Argun , Zhao Ming , Tapia Coya , Scott Stephen M. , Yuca Erkan , Meric-Bernstam Funda 
Published: September 2020

Introduction: A constant challenge in the field of cancer therapeutics is the presence of intrinsic resistance or the development of acquired resistance to chemotherapeutic and targeted agents. One of the approaches to overcome drug resistance is the utilization of combination therapies that simultaneously target several molecules involved in cancer development, progression, and metastasis. Numerous methods are utilized to guide the selection of the appropriate combination therapy. We propose a molecularly guided approach for therapy selection to overcome PARP inhibitor resistance.

Methods: We used a multipronged strategy to characterize triple-negative breast cancer (TNBC) patient-derived xenograft (PDX) models. We identified copy number alterations and pathogenic germline and somatic variants obtained from genomic sequencing. Proteomic and transcriptomic data were analyzed to evaluate gene expression affected by PARP inhibitor therapy. ATM expression status was also determined by immunohistochemistry. Additionally, a comprehensive literature review was performed focused on PARP inhibitor resistance mechanisms to support our rationale for combination therapy selections. We tested selected combination therapies using a cell viability screening assay in PARP inhibitor-resistant TNBC cell lines. Synergistic combinations were tested in vivo in PARP inhibitor-resistant TNBC PDX models.

Results: Model specific pathogenic genomic alterations in PARP inhibitor-resistant TNBC PDX models included genes in the PI3K/AKT/mTOR, DNA damage response, MAPK, and apoptosis signaling pathways. Reverse phase protein array analysis demonstrated differential expression and upregulation of proteins involved in the PI3K/AKT/mTOR and MAPK signaling pathways. Differential gene expression data obtained by RNA sequencing analysis was aggregated to further enhance the individual molecular characterization of PDX models. Subsequently, the antitumor efficacy of selected rational combination therapies was tested in vitro and in vivo.

Conclusions: Our study underscores the importance of a detailed analysis of key molecular biomarkers for therapy selection and proposal of rational combinations to overcome resistance to PARP inhibitors. The translational relevance of this method relies on the potential to recapitulate this approach in patient tumor samples and the opportunity to generate and expand PDX resistant models to test the antitumor efficacy of several rational combinations. Our ultimate goal is to identify the right personalized therapy for the individual cancer patient.

Citation Format: Christian X. Cruz Pico, Kurt W. Evans, Ken Chen, Xiaofeng Zheng, Argun Akcakanat, Ming Zhao, Coya Tapia, Stephen M. Scott, Erkan Yuca, Funda Meric-Bernstam. Overcoming PARP inhibitor resistance with molecularly guided rational combinations in triple-negative breast cancer patient-derived xenograft models [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 676A.