Targeting microtubule sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors
| Autor: | Daniel G. Tenen, Fhu Chee Wai, Elena Levantini, Thomas C. Putti, Wanjin Hong, Eva Csizmadia, Jeff Settleman, John G. Clohessy, Margaret P. Quinlan, Chen Xie, Azhar Ali, Tan Min Chin, Ellen P S Man, Boon Cher Goh, Seow-Ching Wan, Gandhi T K Boopathy, Yan Shan Ong |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Lung Neoplasms Endosome Medicine (miscellaneous) Antineoplastic Agents Mice Transgenic EGFR mutants Magnetic resonance Imaging Molecular pathogenesis of lung cancer NSCLC Immunofluorescence Microtubules chloroquine Drug treatment Mice 03 medical and health sciences 0302 clinical medicine Microtubule Carcinoma Non-Small-Cell Lung Cell Line Tumor Lysosome Chlorocebus aethiops tyrosine kinase inhibitors medicine Animals Humans Protein Kinase Inhibitors Pharmacology Toxicology and Pharmaceutics (miscellaneous) Preclinical murine model of lung cancer medicine.diagnostic_test LAMP1 Chemistry Kinase 3. Good health ErbB Receptors 030104 developmental biology medicine.anatomical_structure Drug Resistance Neoplasm Tumor progression EGFR mutant lung cancer therapy 030220 oncology & carcinogenesis COS Cells Cancer research Lysosomes microtubule dysfunction Research Paper |
| Zdroj: | Theranostics Theranostics 10 (2020): 2727–2743. doi:10.7150/thno.38729 info:cnr-pdr/source/autori:Chin T.-M.; Boopathy G.T.K.; Man E.P.S.; Clohessy J.G.; Csizmadia E.; Quinlan M.P.; Putti T.; Wan S.-C.; Xie C.; Ali A.; Wai F.C.; Ong Y.S.; Goh B.-C.; Settleman J.; Hong W.; Levantini E.; Tenen D.G./titolo:Targeting microtubules sensitizes drug resistant lung cancer cells to lysosomal pathway inhibitors/doi:10.7150%2Fthno.38729/rivista:Theranostics/anno:2020/pagina_da:2727/pagina_a:2743/intervallo_pagine:2727–2743/volume:10 |
| ISSN: | 1838-7640 |
| Popis: | Oncogene-addicted cancers are predominantly driven by specific oncogenic pathways and display initial exquisite sensitivity to designer therapies, but eventually become refractory to treatments. Clear understanding of lung tumorigenic mechanisms is essential for improved therapies. Methods: Lysosomes were analyzed in EGFR-WT and mutant cells and corresponding patient samples using immunofluorescence or immunohistochemistry and immunoblotting. Microtubule organization and dynamics were studied using immunofluorescence analyses. Also, we have validated our findings in a transgenic mouse model that contain EGFR-TKI resistant mutations. Results: We herein describe a novel mechanism that a mutated kinase disrupts the microtubule organization and results in a defective endosomal/lysosomal pathway. This prevents the efficient degradation of phosphorylated proteins that become trapped within the endosomes and continue to signal, therefore amplifying downstream proliferative and survival pathways. Phenotypically, a distinctive subcellular appearance of LAMP1 secondary to microtubule dysfunction in cells expressing EGFR kinase mutants is seen, and this may have potential diagnostic applications for the detection of such mutants. We demonstrate that lysosomal-inhibitors re-sensitize resistant cells to EGFR tyrosine-kinase inhibitors (TKIs). Identifying the endosome-lysosome pathway and microtubule dysfunction as a mechanism of resistance allows to pharmacologically intervene on this pathway. Conclusions: We find that the combination of microtubule stabilizing agent and lysosome inhibitor could reduce the tumor progression in EGFR TKI resistant mouse models of lung cancer. |
| Databáze: | OpenAIRE |
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