Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1

Abstract

Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non-small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLC and NSCLC. SCLC demonstrated lower levels of several receptor tyrosine kinases and decreased activation of PI3K and Ras/MEK pathways, but significantly increased levels of E2F1-regulated factors including EZH2, thymidylate synthase, apoptosis mediators, and DNA repair proteins. Additionally, poly (ADP-ribose) polymerase 1 (PARP1), a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLC. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than NSCLC, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy.

Targeting DNA damage in SCLC

“…A further rationale to target DDR mechanisms comes from knowledge that cancer cells often harbour defects and/or dysregulation of DDR proteins and pathways [34,35]. While there is a paucity of data specific to SCLC, Byers et al [36] conducted an elegant study that identified the DNA repair protein, poly (ADP-ribose) polymerase 1 (PARP 1) as a therapeutic target. A total of 34 SCLC cell lines were profiled for the expression of 193 total and phosphoproteins.…”

“…Preclinical SCLC models were sensitive to PARP inhibition alone and the efficacy of chemotherapy was also enhanced by the addition of a PARP inhibitor [36]. Interestingly, SCLC cell lines revealed comparable or higher chemosensitivity than two breast cancer cell lines with BRCA1 or PTEN mutations, and PARP inhibitor sensitivity correlated with PARP levels [36]. Clinical studies testing several PARP inhibitors are currently ongoing and are discussed below.…”

Molecular Interaction and Inhibitory Potential of Polyphenol on DNA Repair Pathway in Small Cell Lung Cancer: A Computational Study

“…Wealth of studies has vetted PARP-1 as a critical biochemical therapeutic target and was confirmed by reverse phase protein array (RPPA) method, as one of the overexpressed proteins involved in DNA repair pathway in large SCLC proteomic profiling in cell lines [5]. PARP-1 is a chromatinassociated enzyme localized in the nucleus [6][7][8][9], programmed to orchestrate DNA damage resolution symphony, especially in the context of base excision repair (BER) during single-strand (SSB), and double-strand break (DSB) repair, this activation process is a survival mechanism.…”

“…Pharmacologic inhibition of PARP-1 by nascent novels in cancer drug arsenal is the strategy against single-stranded breaks (SSB) and double stranded breaks (DSB) repair machinery by the downregulation of key components of the homologous recombination pathway and which eventually abrogate tumor growth [5] or making the tumour cell more susceptible to chemotherapy. In presence of parp inhibitor, PARP-1 is still recruited to break site, but can no longer activate parp-dependent DNA repair proteins because it catalytic activity can no longer be powered by NAD + binding.…”

Reverse Phase Protein Array: A Tool for Signaling Pathway Profiling in the Era of Genome Resequencing

“…We have been using RPPA as a validation method to determine the clinical utility of candidate serum/plasma biomarker proteins that have been discovered using other proteomics technologies [4]. As an example, Byers et al [5] identified poly(ADP-ribose) polymerase-1 (PARP-1) as a potential therapeutic target for small-cell lung cancer using RPPA.…”