Adaptive Resistance to EGFR-Targeted Therapy by Calcium Signaling in NSCLC Cells
Autor: | Mulder, Celine, Prust, Nadine, Van Doorn, Sander, Reinecke, Maria, Kuster, Bernhard, Van Bergen En Henegouwen, Paul, Lemeer, Simone, Biomolecular Mass Spectrometry and Proteomics, Sub Biomol.Mass Spectrometry & Proteom., Sub Cell Biology, Celbiologie |
---|---|
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Cancer Research Lung Neoplasms Afatinib medicine.medical_treatment Apoptosis Drug resistance Receptor tyrosine kinase Targeted therapy 03 medical and health sciences 0302 clinical medicine Carcinoma Non-Small-Cell Lung Cell Line Tumor Taverne Cell Adhesion medicine Humans Kinome Calcium Signaling Molecular Targeted Therapy Protein Kinase Inhibitors Molecular Biology PI3K/AKT/mTOR pathway EGFR inhibitors Calcium signaling biology business.industry ErbB Receptors 030104 developmental biology Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research biology.protein business medicine.drug |
Zdroj: | Molecular Cancer Research, 16(11), 1773. American Association for Cancer Research Inc. |
ISSN: | 1557-3125 1541-7786 |
Popis: | Targeted therapies against oncogenic receptor tyrosine kinases (RTK) show promising results in the clinic. Unfortunately, despite the initial positive response, most patients develop therapeutic resistance. Most research has focused on acquired resistance occurring after an extensive time of treatment; however, the question remains as to how cells can survive an initial treatment, as early resistance to apoptosis will enable cells to develop any growth-stimulating mechanism. Here, the non–small cell lung cancer (NSCLC) PC9 cell line was used to systematically profile, by mass spectrometry, changes in the proteome, kinome, and phosphoproteome during early treatment with the EGFR inhibitor afatinib. Regardless of the response, initial drug-sensitive cells rapidly adapt to targeted therapy, and within days, cells regained the capacity to proliferate, despite persisting target inhibition. These data reveal a rapid reactivation of mTOR and MAPK signaling pathways after initial inhibition and an increase in abundance and activity of cytoskeleton and calcium signaling–related proteins. Pharmacologic inhibition of reactivated pathways resulted in increased afatinib efficacy. However more strikingly, cells that were restricted from accessing extracellular calcium were extremely sensitive to afatinib treatment. These findings were validated using three additional inhibitors tested in four different NSCLC cell lines, and the data clearly indicated a role for Ca2+ signaling during the development of adaptive resistance. From a therapeutic point of view, the increased inhibitor efficacy could limit or even prevent further resistance development. Implications: Combined targeting of calcium signaling and RTKs may limit drug resistance and improve treatment efficacy. Mol Cancer Res; 16(11); 1773–84. ©2018 AACR. |
Databáze: | OpenAIRE |
Externí odkaz: |