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

Lindsay R Stolzenburg,Paul A Ellis,Bridget Riley-Gillis,Julie L Wilsbacher,Tibor Pakozdi,Cyril Y Ramathal,Areej Ammar,Barrett Ainsworth

doi:10.18632/oncotarget.28162

Lindsay R Stolzenburg, Paul A Ellis + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.28162

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Journal: Oncotarget	Publication Date: Jan 3, 2022
Citations: 5	License type: cc-by

Affiliation: AbbVie (United States)

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.

Highlights

Genome instability is a hallmark of most human malignancies and is linked to the initiation and progression of both inherited and sporadic cancers
Assessment of sensitivity of non-small cell lung cancer (NSCLC) xenograft models to PARPi in combination with cisplatin Potentiation of cisplatin by poly(ADP)-ribose polymerase (PARP) inhibitors has been previously reported in Calu6 and A549 cell lines in vitro and in vivo [15, 23, 24]
By RNA sequencing (RNA-seq) we identified differential gene expression between the combination treatment arm compared to cisplatin alone in Calu6-flank passage x 6 (FP6) tumors

Summary

Introduction

Genome instability is a hallmark of most human malignancies and is linked to the initiation and progression of both inherited and sporadic cancers. Defects in DNA repair pathways, often observed in cancer cells, lead to the use of alternative, error-prone repair mechanisms and directly contribute to genome instability and tumorigenesis. Cells with mutations in BRCA1 or BRCA2 cannot perform DNA double-strand break (DSB) repair by homologous recombination (HR), and accumulate genetic lesions through alternate use of nonhomologous end joining (NHEJ) that directly leads to cancer development [1, 2]. The development of inhibitors to poly(ADP)ribose polymerase 1 (PARP1), an enzyme involved in single-strand break (SSB) repair, have illustrated the feasibility and clinical efficacy of this concept [4,5,6]. PARP1, the most abundant family member, recognizes single base pair lesions, binds to DNA, and synthesizes poly(ADP)-

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