RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer

Kaye, Frederic J.

doi:10.1038/sj.onc.1205834

Cited by 140 publications

(117 citation statements)

References 72 publications

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“…4). This result is in agreement with numerous data published about the cell-cycle checkpoints investigated in this paper and lung cancer (Esposito et al, 1997a;Caputi et al, 1998;Groeger et al, 1999;Mitsudomi et al, 2000;Zhou et al, 2001;Kaye, 2002;Shoji et al, 2002). As expected, the lymph nodes status and clinical tumor stage were significantly correlated with survival as well.…”

Section: The Cell-cycle Machinery and Lung Cancersupporting

confidence: 82%

Role of cell‐cycle regulators in lung cancer

Caputi

Russo

Esposito

et al. 2005

Journal Cellular Physiology

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Lung cancer is the leading cause of cancer death worldwide. Histologically, 80% of lung cancers are classified as non-smallcell lung cancer (NSCLC), and the remaining 20% as small-cell lung cancer (SCLC). Lung carcinoma is the result of molecular changes in the cell, resulting in the deregulation of pathways controlling normal cellular growth, differentiation, and apoptosis. This review summarizes some of the most recent findings about the role of cell-cycle proteins in lung cancer pathogenesis and progression.

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Section: The Cell-cycle Machinery and Lung Cancersupporting

confidence: 82%

Role of cell‐cycle regulators in lung cancer

Caputi

Russo

Esposito

et al. 2005

Journal Cellular Physiology

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“…Thus, we sought to determine the activities of small molecule EGFR inhibitors on EGFRvIII-driven lung tumors in vivo using Tet-op-EGFRvIII͞CCSP-rtTA, Ink4A͞Arf Ϫ/Ϫ mice. The loss of Ink4A͞Arf function in these mice, which recapitulates the frequently reported inactivation of the p16 pathway in human NSCLC (24,25), allows more rapid development of lung tumors (26) (data not shown). Continuous doxycycline administration for Ͼ8 weeks, which caused lung lesions documented by means of MRI (Fig.…”

Section: Resultsmentioning

confidence: 99%

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

Zhao

Yuza

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

233

175

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The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3͞56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0͞123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba͞F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.irreversible inhibitor ͉ lung cancer ͉ lung squamous cell carcinoma E pidermal growth factor receptor (EGFR) is commonly overexpressed and mutated in many human malignancies and is often associated with aggressive phenotypes (1-3). Before the recent discovery of the somatic mutations in the EGFR kinase domain (4-8) in non-small cell lung cancers (NSCLC), deletions of the extracellular domain were considered the most frequent EGFR mutations in the different tumor types (9-13). These deletions have an activating effect on the receptor, giving cells expressing these truncated receptors a proliferative advantage. The most common truncated receptor is the variant III EGFR deletion mutant (EGFRvIII, delta 801EGFR, del2-7 EGFR), containing an inframe deletion of exons 2-7 (801 bp) from the extracellular domain, initially characterized at the genomic level in glioblastoma.Studies using immunohistochemical assays with EGFRvIII mutant-specific antibodies suggest that this mutation is present in multiple other tumor types, including NSCLC (10,11,14). However, because of EGFR's large and complex genomic structure (28 exons spanning Ϸ190 kb) and its large intron 1 (123 kb) where genomic deletions frequently occur, it has been difficult to assess and verify the existence of the EGFRvIII mutations at the genomic level. EGFRvIII mutations have been well demonstrated in glioblastoma, where they are present in Ͼ50% of glioblastomas with amplification of EGFR gene locus (12, 15, 16), but no genomic evidence for the existence of EGFRvIII mutations has been reported in NSCLC. Furthermore, the role of EGFRvIII mutation in the potential pathogenesis of NSCLC is unclear.Here, we report that the EGFRvIII mut...

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“…It is now well known that abnormalities in many positive and negative modulators of the cell cycle are frequent in many cancer types, including lung carcinomas [12,13]. Cyclin D1, a member of the Cyclin D family, regulates the initial G1-to-S transition by inhibiting Rb and activating E2F proteins, and it contributes to cell apoptosis, proliferation, and differentiation [14].…”

Section: Introductionmentioning

confidence: 99%

Diazoxide-Mediated Growth Inhibition in Human Lung Cancer Cells via Downregulation of β-Catenin-Mediated Cyclin D1 Transcription

Ding

Guo

2008

Lung

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Treatment of various types of cells with the mitochondrial ATP-sensitive K ? channel opener, diazoxide, preconditions cells to subsequent injuries and inhibits apoptosis. However, the role and mechanism(s) of diazoxide in solid tumor cell growth are largely unknown. Here we demonstrate that diazoxide inhibited the proliferation of lung cancer cells as well as the transcription of cell cyclerelated protein Cyclin D1. Cyclin D1 overexpression inhibited the negative role of diazoxide in cell cycle progression. We further explored the mechanisms by which diazoxide affected Cyclin D1 transcription and found that the b-catenin transcription factor was downregulated by diazoxide, with a corresponding decrease in Cyclin D1 promoter activity. Taken together, these results suggest that diazoxide inhibits lung cancer cell proliferation via downregulation of Cyclin D1 transcription, which may have important therapeutic implications in lung cancer patients.

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RB and cyclin dependent kinase pathways: defining a distinction between RB and p16 loss in lung cancer

Cited by 140 publications

References 72 publications

Role of cell‐cycle regulators in lung cancer

Role of cell‐cycle regulators in lung cancer

Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors

Diazoxide-Mediated Growth Inhibition in Human Lung Cancer Cells via Downregulation of β-Catenin-Mediated Cyclin D1 Transcription

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