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Master Thesis

Étude des mécanismes de résistance au gefitinib dans le cancer du poumon non-à petites cellules‎ : rôle des HDAC

Abstract : New therapeutic options have to be proposed in order to treat non-small cells lung cancer. In this context EGFR-TKI inhibiting tyrosine kinase activity of epidermal growth factor were developed. However lot of resistance mechanism are observed. Molecular resistance mechanisms affecting the efficiency of tyrosine kinase receptor inhibitors such as gefitinib in non-small cell lung cancer (NSCLC) cells are not fully understood. We have previously showed the involvement of amphiregulin in gefitinib resistance in NSCLC cells, in an acetylation-dependent mechanism. Here, we studied the implication of histone deacetylases (HDACs) in this mechanism. Using HDACs inhibitors, we showed the involvement of class IIb HDACs in gefitinib-induced apoptosis inhibition mediated by amphiregulin in NSCLC cells. Class IIb HDAC6 inhibition by tubastatin A or siRNA failed to restore gefitinib-induced apoptosis. We observed that HDAC6 inhibition increased the level of activation of PI3K/AKT and MAPK/ERK1/2. Cotreatment of NSCLC cells with gefitinib and HDAC6 inhibition decreased MAPK/ERK1/2 activation, but not PI3K/AKT level, suggesting that PI3K/AKT survival pathways could protect cells from HDAC6 inhibition. Altogether, our results suggested that HDAC6 inhibition cannot prevent gefitinib resistance in NSCLC cells and that PI3K/AKT survival pathway may compensate HDAC6 inhibition.
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Master Thesis
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https://dumas.ccsd.cnrs.fr/dumas-00708589
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Submitted on : Tuesday, August 21, 2012 - 4:43:37 PM
Last modification on : Wednesday, July 15, 2020 - 8:56:03 AM

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  • HAL Id : dumas-00708589, version 1

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Victor Jeannot. Étude des mécanismes de résistance au gefitinib dans le cancer du poumon non-à petites cellules‎ : rôle des HDAC. Sciences pharmaceutiques. 2012. ⟨dumas-00708589⟩

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