Predictive Value of BRCA1, ERCC1, ATP7B, PKM2, TOPOI, TOPΟ-IIA, TOPOIIB and C-MYC Genes in Patients with Small Cell Lung Cancer (SCLC) Who Received First Line Therapy with Cisplatin and Etoposide

Karachaliou, Niki; Papadaki, Chara; Lagoudaki, Eleni; Trypaki, Maria; Sfakianaki, Maria; Koutsopoulos, Anastasios; Mavroudis, Dimitris; Stathopoulos, Efstathios N.; Georgoulias, Vassilis; Souglakos, John

doi:10.1371/journal.pone.0074611

Cited by 31 publications

(34 citation statements)

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“…Patients with signet ring cell gastric cancer displayed a poor prognosis when their levels of PKM2 were elevated [26]. In small cell lung cancer, high expression of PKM2 was correlated with decreased median overall survival, and it may predict treatment outcome in patients with small cell lung cancer [27]. By showing that PKM2 expression is increased in ESCC tissues as well as in the serum of patients with Kazakh's ESCC, our study confirms the potential value of PKM2 as a biomarker for cancer and extends it to the esophagus, a location especially poor in biomarkers.…”

Section: Discussionmentioning

confidence: 99%

M2 isoform of pyruvate kinase (PKM2) is upregulated in Kazakh’s ESCC and promotes proliferation and migration of ESCC cells

et al. 2015

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The objectives of the present study are to explore role of pyruvate kinase isoenzyme type M2 (PKM2) in progression of Kazakh's esophageal squamous cell carcinoma (ESCC) in Xinjiang, China, and to clarify mechanism of PKM2 in malignant phenotype. PKM2 expression was examined using immunohistochemistry (IHC) in 101 matched pairs of ESCC and normal adjacent tissues (NATs) and using enzyme-linked immunosorbent assay (ELISA) in 35 serum samples of Kazakh's ESCC and 8 serum samples of healthy subjects. To investigate mechanism, small interfering RNA (siRNA)-PKM2 was transfected into ESCC cells. Cell migration and invasion were evaluated by wound healing and Transwell assays. Apoptosis and cell cycle were analyzed by flow cytometry (FCM). PKM2 expression was significantly higher in ESCC tissues (77.2 %, 78/101) compared with matched NAT (P = 0.003) and also higher in serum samples of Kazakh's ESCC patients (78.84 ng/mL) compared with healthy subjects (13.55 ng/mL) (P = 0.001). Patients with overexpression of PKM2 had a poor prognosis (P = 0.032). After knockdown of PKM2, cell proliferation, migration, and invasion were significantly reduced (P = 0.001), apoptosis increased (P = 0.001), and cell cycle was arrested at G1 phase. PKM2 overexpression was significantly correlated with the worse outcome of Kazakh's ESCC. Furthermore, PKM2 was involved in progression of ESCC by promoting proliferation and suppressing apoptosis, accelerating invasion, and influencing cell cycle. PKM2 could be a potential biomarker for molecular classification of ESCC.

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Section: Discussionmentioning

confidence: 99%

M2 isoform of pyruvate kinase (PKM2) is upregulated in Kazakh’s ESCC and promotes proliferation and migration of ESCC cells

et al. 2015

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“…Low ERCC1 expression in tumours is associated with a higher response rate and longer survival of SCLC patients with limited disease (LD) [31,32]. With respect to mechanisms of resistance to other cytotoxics, etoposide and topotecan inhibit the topoisomerase enzymes II and I respectively, culminating in DNA DSBs.…”

Section: Foy Et Almentioning

confidence: 99%

“…With respect to mechanisms of resistance to other cytotoxics, etoposide and topotecan inhibit the topoisomerase enzymes II and I respectively, culminating in DNA DSBs. Studies by Dingemans et al and Karachaliou et al demonstrate a correlation between the survival of SCLC patients and the expression of DNA Topoisomerase I and II [32,33]. High expression of TOPI, TOPIIA, and TOPIIB is associated with a shorter PFS in LD patients, whereas high expression of TOPIIB is associated with low response rates [32,33].…”

Section: Foy Et Almentioning

confidence: 99%

“…Studies by Dingemans et al and Karachaliou et al demonstrate a correlation between the survival of SCLC patients and the expression of DNA Topoisomerase I and II [32,33]. High expression of TOPI, TOPIIA, and TOPIIB is associated with a shorter PFS in LD patients, whereas high expression of TOPIIB is associated with low response rates [32,33]. Although circumstantial, these findings implicate a role for DDR mechanisms in chemoresistance.…”

Section: Foy Et Almentioning

confidence: 99%

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Targeting DNA damage in SCLC

et al. 2017

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A B S T R A C TSCLC accounts for 15% of lung cancer worldwide. Characterised by early dissemination and rapid development of chemo-resistant disease, less than 5% of patients survive 5 years. Despite 3 decades of clinical trials there has been no change to the standard platinum and etoposide regimen for first line treatment developed in the 1970's.The exceptionally high number of genomic aberrations observed in SCLC combined with the characteristic rapid cellular proliferation results in accumulation of DNA damage and genomic instability. To flourish in this precarious genomic context, SCLC cells are reliant on functional DNA damage repair pathways and cell cycle checkpoints.Current cytotoxic drugs and radiotherapy treatments for SCLC have long been known to act by induction of DNA damage and the response of cancer cells to such damage determines treatment efficacy. Recent years have witnessed improved understanding of strategies to exploit DNA damage and repair mechanisms in order to increase treatment efficacy.This review will summarise the rationale to target DNA damage response in SCLC, the progress made in evaluating novel DDR inhibitors and highlight various ongoing challenges for their clinical development in this disease.

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“…It facilitates efficient processing of double-strand DNA breaks (DSB) to single-strand ends and sustains DNA damage signaling. The predictive value of the expression of DNA repair genes on the response and survival of SCLC patients treated with chemotherapy has been previously reported (17). When ARID1A is lost, the DNA DSBs repair process is impaired and tumor cells are sensitized to DSB-inducing therapies such as radiation or PARP inhibitors (18).…”

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confidence: 95%