Transcriptomics reveals in vivo efficacy of PARP inhibitor combinatorial synergy with platinum-based chemotherapy in human non-small cell lung carcinoma models

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// Lindsay R. Stolzenburg 1 , * , Barrett Ainsworth 1 , * , Bridget Riley-Gillis 1 , Tibor Pakozdi 1 , Areej Ammar 1 , Paul A. Ellis 1 , Julie L. Wilsbacher 1 and Cyril Y. Ramathal 1 1 AbbVie Inc., North Chicago, IL 60064, USA * These authors contributed equally to this work Correspondence to: Cyril Y. Ramathal, email: cyril.ramathal@abbvie.com Keywords: PARP inhibitor; veliparib; cisplatin; transcriptomics; NSCLC Abbreviations: PARP: poly(ADP)-ribose polymerase; PARPi: poly(ADP)-ribose polymerase inhibitors; NSCLC: non-small cell lung cancer; DEGs: differentially expressed genes Received: November 19, 2021 Accepted: December 10, 2021 Published: PUBLISHED_DATE Copyright: © 2021 Stolzenburg et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT Inhibitors of poly(ADP)-ribose polymerase (PARP) exploit defective DNA repair pathways existing in several forms of cancer, such as those with BRCA mutations, and have proven clinical efficacy as chemosensitizers. However, platinum-based chemopotentiation by PARP inhibitors (PARPi), particularly for non-small cell lung cancer (NSCLC), has only been confirmed in a few preclinical models and the molecular mechanisms that drive PARPi combinatorial synergy with chemotherapeutics remains poorly defined. To better understand these mechanisms, we characterized cisplatin and veliparib efficacy in A549 and Calu6 NSCLC in vivo tumor xenograft models and observed combinatorial synergy in the Calu6 model. Transcriptome-wide analysis of xenografts revealed several differentially expressed genes (DEGs) between untreated and cisplatin + veliparib-treated groups, which were unique from genes identified in either of the single-agent treatment arms. Particularly at 10- and 21-days post-treatment, these DEGs were enriched within pathways involved in DNA damage repair, cell cycle regulation, and senescence. Furthermore, TGF-β- and integrin-related pathways were enriched in the combination treatment arm, while pathways involved in cholesterol metabolism were identified at earlier time points in both the combination and cisplatin-only groups. These data advance the biological underpinnings of PARPi combined with platinum-based chemotherapy and provides additional insight into the diverse sensitivity of NSCLC models.