mRNA expression levels and genetic status of genes involved in the EGFR and NF-κB pathways in metastatic non-small-cell lung cancer patients

Santarpía, Mariacarmela; Magrí, Ignacio; Sanchez-Ronco, María; Costa, Carlota; Molina-Vila, Miguel Ángel; Giménez‐Capitán, Ana; Bertrán-Alamillo, Jordi; Mayo, Clara; Benlloch, Susana; Viteri, Santiago; Gasco, Amaya; Mederos, Nuria; Carcereny, Enric; Tarón, Miquel; Rosell, Rafael

doi:10.1186/1479-5876-9-163

Cited by 25 publications

(14 citation statements)

References 34 publications

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“…It could be of interest to examine the EZH2:BRCA1 mRNA ratio in SCLC patients, although in the report by the Heymach group ( 3 ), it seems that BRCA1 and EZH2 could both be overexpressed. In our experience, the expression of both BRCA1 and EZH2 was signifi cantly higher in SCLC than in NSCLC patient tumors ( 11 ). Therefore, the inverse relationship observed in breast cancer may not hold true for SCLC.…”

Section: A Genetic Snapshot Of Small Cell Lung Cancermentioning

confidence: 73%

A Genetic Snapshot of Small Cell Lung Cancer

Rosell

Wannesson

2012

Cancer Discovery

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Small cell lung cancer (SCLC) represents 13% of all newly diagnosed cases of cancer worldwide, or more than 180,000 cases per year. In contrast with non-small cell lung cancer (NSCLC), it is not associated with specifi c somatic mutations ( 1 ). The prognosis for patients with SCLC has not improved and treatment has remained substantially the same for the last 25 years. The fi rst-line treatment of choice in extensivestage SCLC is 4 to 6 cycles of etoposide combined with cisplatin or carboplatin, with a median survival of 8 to 13 months and a 2-year survival rate of 5%. For patients with limitedstage disease, the standard treatment is the same chemotherapy regimen with the addition of thoracic radiotherapy, and median survival is 15 to 20 months, with a 2-year survival rate of 20% to 40% ( 1 ). The RB and TP53 tumor suppressor genes are both mutated in more than 90% of human SCLCs. Recent data indicate that p130 mRNA levels are downregulated in SCLC. Similarly, loss of E2F4, a major partner for p130, partially suppresses lung neuroendocrine hyperplasias in RBmutant mice. The loss of p130 accelerates the development of SCLC in RB / TP53 -mutant mice ( 2 ).In this issue of Cancer Discovery , Byers and colleagues ( 3 ) identify signifi cant differences in signaling pathways between SCLC and NSCLC. Using reverse phase protein arrays, they studied the expression of 193 proteins in 34 SCLC and 74 NSCLC cell lines. PARP1 and enhancer of zeste homolog 2 (EZH2) were 2 of the most overexpressed proteins in SCLC. SCLC growth was abrogated by knockdown of PARP1 and EZH2. Intriguingly, SCLC cell lines were signifi cantly more sensitive to PARP inhibitors than were NSCLC cell lines. PARP inhibition downregulated key components of the homologous recombination pathway, such as RAD51 and BRCA1. The authors observed lower levels of total and IN THE SPOTLIGHT A Genetic Snapshot of Small Cell Lung Cancer Commentary on Byers et al., p. 798 (3).phospho-Rb and higher levels of E2F1 in SCLC than in NSCLC cell lines. They posit that because of the loss of RB, E2F1 expression leads to the activation of several E2F1 targets in SCLC cells, such as EZH2, thymidylate synthase (TS), and several components of DNA repair pathways, including 53BP1 ( 3 ). In contrast, NSCLC cells had higher expression of receptor tyrosine kinases that heterodimerize with EGFR, including HER2, MET, and AXL. The differential expression of PARP1 was confi rmed by Western blotting and by mRNA analysis. The mRNA levels in SCLC were higher for PARP1, EZH2, BCL2, PRKDC (DNA PKcs), and proliferating cell nuclear antigen ( PCNA ). PARP1 expression was also examined in 318 cell lines derived from 30 types of primary cancer. Interestingly, SCLC cells showed the highest PARP1 expression. Immunohistochemistry confi rmed that PARP1 was more highly expressed in SCLC than in NSCLC. The most intriguing fi nding is that the majority of SCLC cells were sensitive to the use of PARP inhibitors, such as AZD2281, in contrast to the majority of NSCLC cell lines, which were resistant, i...

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Section: A Genetic Snapshot Of Small Cell Lung Cancermentioning

confidence: 73%

A Genetic Snapshot of Small Cell Lung Cancer

Rosell

Wannesson

2012

Cancer Discovery

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“…In literature, there is only one report showing that low levels of MTDH also occur in pathological conditions (Santarpia et al, 2011). As demonstrated by Santarpia et al in metastatic NSCLC, patients with low levels of both BRCA1 and AEG-1 showed significant improved progression-free survival (PFS) compared to those with…”

Section: Discussionmentioning

confidence: 98%

Deregulation of MTDH Gene Expression in Gastric Cancer

Emadi‐Baygi

Nikpour²

2012

Asian Pacific Journal of Cancer Prevention

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Aim: Gastric cancer is the third most frequent cause of cancer mortality worldwide. In Iran, it is one of the leading causes at the national level. Localized at chromosome 8q22, the human MTDH gene has been reported to be over-expressed in a spectrum of malignancies. However, since there is a lack of data concerning with expression in gastric cancer at the transcriptional level, in this study we evaluated MTDH expression in Iranian cases. Methods: Totally, thirty paired gastric samples were examined by quantitative real-time RT-PCR. Results: Although the mRNA expression was significantly elevated in 46.6% of the examined tumor tissues; its expression was low in others (36.6%). Moreover, there was only a marginal statistical difference between the MTDH gene expression of all tumor specimens compared to their paired non-tumor ones and no statistically significant association with the grades and types of the tumors. Conclusion: Taken together, our results demonstrated that expression of MTDH at the transcriptional level may be increased in gastric cancer tissue samples but with considerable heterogeneity. Due to this, it may have the potential to be used as a target for diagnostic/therapeutic purposes only in a subset of patients.

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“…This suggests that establishing the presence of the T790M mutation and BRCA1 levels could aid appropriate treatment selection for such patients [25]. Furthermore, the coexpression of BRCA1 and the associated oncogene, astrocyte elevated gene-1, could represent a marker for prognosis in patients with wild-type EGFR and response to erlotinib treatment in patients with EGFR mutations [30].…”

Section: Basal T790m Mutationsmentioning

confidence: 99%

Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors

Rolfo

Giovannetti

Hong

et al. 2014

Cancer Treatment Reviews

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a b s t r a c tIntroduction: Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) yields tumour responses in non-small cell lung cancer (NSCLC) patients harbouring activating EGFR mutations. However, even in long-lasting responses, resistance to EGFR TKIs invariably occurs. Areas covered: This review examines resistance mechanisms to EGFR TKI treatment, which mainly arise from secondary EGFR mutations. Other resistance-inducing processes include mesenchymal-epithelial transition factor (MET) amplification, epithelial-mesenchymal transformation, phenotypic change from NSCLC to small-cell lung carcinoma, and modifications in parallel signalling pathways. Current therapeutic strategies to overcome these EGFR TKI resistance mechanisms focus on the inhibition or blocking of multiple members of the ErbB family. Several molecules which target multiple ErbB receptors are being investigated in NSCLC and other indications including afatinib, an ErbB Family Blocker, as well as dacomitinib and lapatinib. Novel, non-quinazoline, EGFR inhibitors, that also target EGFR activating and resistance (T790M) mutations, are currently under clinical development. Other therapeutic strategies include inhibition of parallel and downstream pathways, using agents which target heat shock protein (HSP)90 or http://dx.doi.org/10.1016/j.ctrv.2014.05.009 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved.Abbreviations: AEG-1, astrocyte elevated gene-1; ALK, anaplastic lymphoma kinase; ATP, adenosine triphosphate; BARD1, BRCA1-associated protein 1; BIM, B-cell lymphoma 2 interacting mediator of cell death; BRAF, v-raf murine sarcoma viral oncogene homolog B1; BRCA1, breast cancer 1, early onset; CNS, central nervous system; CRKL, crk-like protein; DCR, disease control rate; EGFR, epidermal growth factor receptor; EMT, epithelial-mesenchymal transformation; EphB4, ephrin type-B receptor 4; ER, oestrogen receptor; ERK, extracellular-signal-regulated kinases; HER, human epidermal growth factor receptor; HGF, hepatocyte growth factor; HSP90, heat shock protein 90; IGF-1R, insulin-like growth factor 1 receptor; KRAS, Kirsten rat sarcoma viral oncogene homologue; MBP-QP, mutation-biased PCR quenching probe; MEK, mitogen-activated protein kinase; MET, mesenchymal-epithelial transition factor; mRNA, messenger RNA; mTOR, mammalian target of rapamycin; NF-jB, nuclear factor kappa-light-chainenhancer of activated B cells; NSCLC, non-small-cell lung cancer; ORR, overall response rate; OS, overall survival; PARP, poly (ADP-ribose) polymerase; PCR, polymerase chain reaction; PFS, progression free survival; PI3K, phosphoinositide-3-kinase; PIK3CA, phosphoinositide-3-kinase, catalytic, alpha polypeptide; PTEN, phosphatase and tensin homologue; RECIST, Response Evaluation Criteria in Solid Tumours; RR, response rate; SCLC, small-cell lung cancer; TGF, transforming growth factor; TKI, tyrosine kinase inhibitors; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor. E-mail address: christian.rolfo@uza.be (C. Rolfo).Can...

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mRNA expression levels and genetic status of genes involved in the EGFR and NF-κB pathways in metastatic non-small-cell lung cancer patients

Cited by 25 publications

References 34 publications

A Genetic Snapshot of Small Cell Lung Cancer

A Genetic Snapshot of Small Cell Lung Cancer

Deregulation of MTDH Gene Expression in Gastric Cancer

Novel therapeutic strategies for patients with NSCLC that do not respond to treatment with EGFR inhibitors

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