Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells
| العنوان: | Intrinsic resistance to selumetinib, a selective inhibitor of MEK1/2, by cAMP-dependent protein kinase A activation in human lung and colorectal cancer cells |
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| المؤلفون: | Sarah Costantino, Teresa Troiani, Liberato Berrino, Anna Capasso, Donata Vitagliano, M. De Lorenzi, Sabine Tejpar, Erika Martinelli, Elena D'Aiuto, Michele Caraglia, Ludovica Ciuffreda, Loredana Vecchione, E. Van Cutsem, Floriana Morgillo, Fortunato Ciardiello, R. De Palma |
| المساهمون: | Troiani, Teresa, Vecchione, L, Martinelli, Erika, Capasso, A, Costantino, S, Ciuffreda, Lp, Morgillo, Floriana, Vitagliano, D, D'Aiuto, E, DE PALMA, Raffaele, Tejpar, S, Van Cutsem, E, De Lorenzi, M, Caraglia, Michele, Berrino, Liberato, Ciardiello, Fortunato |
| المصدر: | British Journal of Cancer |
| بيانات النشر: | Springer Science and Business Media LLC, 2012. |
| سنة النشر: | 2012 |
| مصطلحات موضوعية: | Cancer Research, Lung Neoplasms, Colorectal cancer, Apoptosis, selumetinib, PKA, gene expression, gene mutations, cancer cell resistance, Mitogen-activated protein kinase kinase, Gene mutation, Biology, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Humans, gene mutation, Protein kinase A, Cell Proliferation, 030304 developmental biology, Mitogen-Activated Protein Kinase Kinases, 0303 health sciences, Cell growth, Gene Expression Profiling, Cell Cycle, Cell cycle, medicine.disease, Cyclic AMP-Dependent Protein Kinases, Xenograft Model Antitumor Assays, 3. Good health, Enzyme Activation, Oncology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Mutation, Selumetinib, Cancer research, Benzimidazoles, Colorectal Neoplasms, Translational Therapeutics |
| الوصف: | Background: MEK is activated in ∼40% colorectal cancer (CRC) and 20–30% non-small cell lung cancer (NSCLC). Selumetinib is a selective inhibitor of MEK1/2, which is currently in clinical development. Methods: We evaluated the effects of selumetinib in vitro and in vivo in CRC and NSCLC cell lines to identify cancer cell characteristics correlating with sensitivity to MEK inhibition. Results: Five NSCLC and six CRC cell lines were treated with selumetinib and classified according to the median inhibitory concentration (IC50) values as sensitive (⩽1 μℳ) or resistant (>1 μℳ). In selumetinib-sensitive cancer cell lines, selumetinib treatment induced G1 cell-cycle arrest and apoptosis and suppression of tumour growth as xenografts in immunodeficient mice. Evaluation of intracellular effector proteins and analysis of gene mutations showed no correlation with selumetinib sensitivity. Microarray gene expression profiles revealed that the activation of cAMP-dependent protein kinase A (PKA) was associated with MEK inhibitor resistance. Combined targeting of both MEK and PKA resulted in cancer cell growth inhibition of MEK inhibitor-resistant cancer cell lines in vitro and in vivo. Conclusion: This study provides molecular insights to explain resistance to an MEK inhibitor in human cancer cell lines. |
| تدمد: | 1532-1827 0007-0920 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::27c2beb4f13012f112125cd8e2488524Test https://doi.org/10.1038/bjc.2012.129Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....27c2beb4f13012f112125cd8e2488524 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15321827 00070920 |
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