Targeting protein translation in human non-small cell lung cancer via combined MEK and mammalian target of rapamycin suppression

Marie Emmanuelle Legrier, Chia-Ping H. Yang, Han Guang Yan, Lluis Lopez-Barcons, Steven M. Keller, Roman Perez-Soler, Susan Band Horwitz, Hayley M. McDaid

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Lung cancer is a genetically heterogeneous disease characterized by the acquisition of somatic mutations in numerous protein kinases, including components of the rat sarcoma viral oncogene homolog (RAS) and AKT signaling cascades. These pathways intersect at various points, rendering this network highly redundant and suggesting that combined mitogen-activated protein/extracellular signal-regulated kinase (MEK) and mammalian target of rapamycin (mTOR) inhibition may be a promising drug combination that can overcome its intrinsic plasticity. The MEK inhibitors, CI-1040 or PD0325901, in combination with the mTOR inhibitor, rapamycin, or its analogue AP23573, exhibited dose-dependent synergism in human lung cancer cell lines that was associated with suppression of proliferation rather than enhancement of cell death. Concurrent suppression of MEK and mTOR inhibited ribosomal biogenesis by 40% within 24 h and was associated with a decreased polysome/monosome ratio that is indicative of reduced protein translation efficiency. Furthermore, the combination of PD0325901 and rapamycin was significantly superior to either drug alone or PD0325901 at the maximum tolerated dose in nude mice bearing human lung tumor xenografts or heterotransplants. Except for a PTEN mutant, all tumor models had sustained tumor regressions and minimal toxicity. These data (a) provide evidence that both pathways converge on factors that regulate translation initiation and (b) support therapeutic strategies in lung cancer that simultaneously suppress the RAS and AKT signaling network.

Original languageEnglish (US)
Pages (from-to)11300-11308
Number of pages9
JournalCancer Research
Volume67
Issue number23
DOIs
StatePublished - Dec 1 2007

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Mitogen-Activated Protein Kinase Kinases
Protein Biosynthesis
Sirolimus
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Heterografts
Neoplasms
Polyribosomes
Maximum Tolerated Dose
Extracellular Signal-Regulated MAP Kinases
Drug Combinations
Mitogens
Oncogenes
Nude Mice
Sarcoma
Protein Kinases
Cell Death
Cell Line
Lung
Mutation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Targeting protein translation in human non-small cell lung cancer via combined MEK and mammalian target of rapamycin suppression. / Legrier, Marie Emmanuelle; Yang, Chia-Ping H.; Yan, Han Guang; Lopez-Barcons, Lluis; Keller, Steven M.; Perez-Soler, Roman; Band Horwitz, Susan; McDaid, Hayley M.

In: Cancer Research, Vol. 67, No. 23, 01.12.2007, p. 11300-11308.

Research output: Contribution to journalArticle

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