Two Novel Determinants of Etoposide Resistance in Small Cell Lung Cancer

Abstract

Patient survival in small cell lung cancer (SCLC) is limited by acquired chemoresistance. Here we report the use of a biologically relevant model to identify novel candidate genes mediating in vivo acquired resistance to etoposide. Candidate genes derived from a cDNA microarray analysis were cloned and transiently overexpressed to evaluate their potential functional roles. We identified two promising genes in the DNA repair enzyme DNA polymerase b and in the neuroendocrine transcription factor NKX2.2. Specific inhibition of DNA polymerase b reduced the numbers of cells surviving treatment with etoposide and increased the amount of DNA damage in cells. Conversely, stable overexpression of NKX2.2 increased cell survival in response to etoposide in SCLC cell lines. Consistent with these findings, we found that an absence of nuclear staining for NKX2.2 in SCLC primary tumors was an independent predictor of improved outcomes in chemotherapy-treated patients. Taken together, our findings justify future prospective studies to confirm the roles of these molecules in mediating chemotherapy resistance in SCLC. Cancer Res; 71(14); 4877-87. Ó2011 AACR.

CD133+ Cancer Stem-like Cells in Small Cell Lung Cancer Are Highly Tumorigenic and Chemoresistant but Sensitive to a Novel Neuropeptide Antagonist

“…The GLC14 and GLC16 cell lines are SCLC cells that have been established from a single patient during the progression of chemoresitance (25). The GLC16 line has subsequently been shown to be more chemoresistant than the GLC14 cells (26). We have shown previously that the GLC16 line expresses more neuropeptide receptors, which correlates with an increased response to SP-G (22).…”

“…SCLC cells; NCI-H69 and NCI-H345 (European Collection of Animal Cell Cultures, Health Protection Agency, Porton Down, United Kingdom) and GLC14 and GLC16 cells (22,25) grew as free floating aggregates and were positive for neuronal adhesion molecule by Western blot analysis. The GLC14 and GLC16 cells were previously profiled by short tandem repeat profiling to confirm their origin from a single patient (25,26). GRP-R-and V 1A -Rexpressing CHO-K1 cells (23) were confirmed receptor positive by Western blot analysis.…”

Targeting DNA Flap Endonuclease 1 to Impede Breast Cancer Progression

“…However, the high efficiency of DNA repair due to the overexpression of DNA repair proteins in cancer cells reduces the drug efficacy significantly (Fink et al, 1996, Fink et al, 1998). For example, the expression level of DNA polymerase beta (Pol β) has been correlated with resistance of cancer cells to chemotherapeutic drugs (Lawson et al, 2011). Cells with higher levels of DNA ligase IV exhibit reduced levels of γ-H2AX foci (an early marker of DNA damage in cells) upon treatment with DNA damage agents (Srivastava et al, 2012).…”

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

“…There is a typical disease trajectory with an initial good clinical response followed by rapid relapse of chemoresistant tumour and death [4]. Because surgical resection is not part of standard care, SCLC research using primary tumour tissue is limited to small diagnostic samples and, thus, the therapeutic benefits from the molecular analysis of this tumours are limited during the last 30 years [5]. …”