Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling

Susumu Kobayashi, Takeshi Shimamura, Stefano Monti, Ulrich G. Steidl, Christopher J. Hetherington, April M. Lowell, Todd Golub, Matthew Meyerson, Daniel G. Tenen, Geoffrey L. Shapiro, Balazs Halmos

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

Activating mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain determine responsiveness to EGFR tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer (NSCLC). The modulation of transcriptional pathways by mutant EGFR signaling is not fully understood. Previously, we and others identified a single base pair change leading to a threonine to methionine (T790M) amino acid alteration in the ATP-binding pocket of the EGFR as a common mechanism of acquired resistance. The gefitinib-resistant, T790M-mutant H1975 NSCLC cell line undergoes prominent growth arrest and apoptosis when treated with the irreversible EGFR inhibitor, CL-387,785. We did a transcriptional profiling study of mutant EGFR target genes that are differentially expressed in the "resistant" gefitinib-treated and the "sensitive" CL387,785-treated H1975 cells to identify the pivotal transcriptional changes in NSCLC with EGFR-activating mutations. We identified a small subset of early gene changes, including significant reduction of cyclin D1 as a result of EGFR inhibition by CL-387,785 but not by gefitinib. The reduction in cyclin D1 transcription was associated with subsequent suppression of E2F-responsive genes, consistent with proliferation arrest. Furthermore, cyclin D1 expression was higher in EGFR-mutant lung cancer cells compared with cells with wild-type EGFR. EGFR-mutant cells were routinely sensitive to the cyclin-dependent kinase inhibitor flavopiridol, confirming the functional relevance of the cyclin D axis. These studies suggest that cyclin D1 may contribute to the emergence of EGFR-driven tumorigenesis and can be an alternative target of therapy.

Original languageEnglish (US)
Pages (from-to)11389-11398
Number of pages10
JournalCancer Research
Volume66
Issue number23
DOIs
StatePublished - Dec 1 2006
Externally publishedYes

Fingerprint

Cyclin D1
Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
alvocidib
Protein-Tyrosine Kinases
Cyclin D
erbB-1 Genes
Mutation
Cyclin-Dependent Kinases
Threonine
Complementary Therapies
Base Pairing
Methionine
Genes
Lung Neoplasms
Carcinogenesis
Adenosine Triphosphate
Apoptosis
Amino Acids
Cell Line

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling. / Kobayashi, Susumu; Shimamura, Takeshi; Monti, Stefano; Steidl, Ulrich G.; Hetherington, Christopher J.; Lowell, April M.; Golub, Todd; Meyerson, Matthew; Tenen, Daniel G.; Shapiro, Geoffrey L.; Halmos, Balazs.

In: Cancer Research, Vol. 66, No. 23, 01.12.2006, p. 11389-11398.

Research output: Contribution to journalArticle

Kobayashi, S, Shimamura, T, Monti, S, Steidl, UG, Hetherington, CJ, Lowell, AM, Golub, T, Meyerson, M, Tenen, DG, Shapiro, GL & Halmos, B 2006, 'Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling', Cancer Research, vol. 66, no. 23, pp. 11389-11398. https://doi.org/10.1158/0008-5472.CAN-06-2318
Kobayashi, Susumu ; Shimamura, Takeshi ; Monti, Stefano ; Steidl, Ulrich G. ; Hetherington, Christopher J. ; Lowell, April M. ; Golub, Todd ; Meyerson, Matthew ; Tenen, Daniel G. ; Shapiro, Geoffrey L. ; Halmos, Balazs. / Transcriptional profiling identifies cyclin D1 as a critical downstream effector of mutant epidermal growth factor receptor signaling. In: Cancer Research. 2006 ; Vol. 66, No. 23. pp. 11389-11398.
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