Abstract
Irinotecan is a major drug for treatment of metastatic colorectal cancer and a promising agent for other applications like gastric cancer. Its clinical activity is currently limited by both intrinsic (natural) and acquired drug resistance. A better understanding of the underlying resistance mechanisms is needed to develop novel therapeutic strategies. Exposure of tumor cells to irinotecan or its active metabolite SN-38 is accompanied by EGFR activation, either by stimulation of EGFR autophosphorylation or by Src-mediated phosphorylation. Accordingly, combinations of irinotecan and EGFR inhibitors have been associated with supra-additive activity. We now show that acquired resistance to SN-38 is accompanied by increased expression of EGFR, HER2, HER3 and Src proteins in two colorectal cancer cell models as well as by Src activation. One SN-38 resistant model (HT-29) showed increased sensitivity to erlotinib, an EGFR inhibitor, and afatinib, a dual EGFR/HER2 inhibitor, while the other SN-38 resistant model (HCT-116) showed increased resistance to erlotinib but unchanged or increased sensitivity to afatinib. Unexpectedly, both models showed increased or unaltered resistance to the Src inhibitor dasatinib. Therefore, tyrosine kinase upregulation is not necessarily accompanied by increased sensitivity to targeted agents. Taken together, our findings demonstrate that prolonged exposure to topoisomerase I inhibitors is accompanied by upregulation of different signal transduction pathways which can alter tumor sensitivity to molecular targeted agents. These results suggest that chemotherapy exposure may lead to creation of novel targets which could be exploited therapeutically.
Keywords: Topoisomerase I, EGFR, Src, irinotecan, SN-38, erlotinib, afatinib, dasatinib, colorectal cancer, autophosphorylation
Current Pharmaceutical Design
Title:Irinotecan Resistance is Accompanied by Upregulation of EGFR and Src Signaling in Human Cancer Models
Volume: 19 Issue: 5
Author(s): Amelie Petitprez and Annette K. Larsen
Affiliation:
Keywords: Topoisomerase I, EGFR, Src, irinotecan, SN-38, erlotinib, afatinib, dasatinib, colorectal cancer, autophosphorylation
Abstract: Irinotecan is a major drug for treatment of metastatic colorectal cancer and a promising agent for other applications like gastric cancer. Its clinical activity is currently limited by both intrinsic (natural) and acquired drug resistance. A better understanding of the underlying resistance mechanisms is needed to develop novel therapeutic strategies. Exposure of tumor cells to irinotecan or its active metabolite SN-38 is accompanied by EGFR activation, either by stimulation of EGFR autophosphorylation or by Src-mediated phosphorylation. Accordingly, combinations of irinotecan and EGFR inhibitors have been associated with supra-additive activity. We now show that acquired resistance to SN-38 is accompanied by increased expression of EGFR, HER2, HER3 and Src proteins in two colorectal cancer cell models as well as by Src activation. One SN-38 resistant model (HT-29) showed increased sensitivity to erlotinib, an EGFR inhibitor, and afatinib, a dual EGFR/HER2 inhibitor, while the other SN-38 resistant model (HCT-116) showed increased resistance to erlotinib but unchanged or increased sensitivity to afatinib. Unexpectedly, both models showed increased or unaltered resistance to the Src inhibitor dasatinib. Therefore, tyrosine kinase upregulation is not necessarily accompanied by increased sensitivity to targeted agents. Taken together, our findings demonstrate that prolonged exposure to topoisomerase I inhibitors is accompanied by upregulation of different signal transduction pathways which can alter tumor sensitivity to molecular targeted agents. These results suggest that chemotherapy exposure may lead to creation of novel targets which could be exploited therapeutically.
Export Options
About this article
Cite this article as:
Petitprez Amelie and K. Larsen Annette, Irinotecan Resistance is Accompanied by Upregulation of EGFR and Src Signaling in Human Cancer Models, Current Pharmaceutical Design 2013; 19 (5) . https://dx.doi.org/10.2174/1381612811306050958
DOI https://dx.doi.org/10.2174/1381612811306050958 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Targeting Poly (ADP) Ribose Polymerase I (PARP-1) and PARP-1 Interacting Proteins for Cancer Treatment
Anti-Cancer Agents in Medicinal Chemistry A Review on the Techniques for Characterizing and Predicting Human Genomic DNA Methylation
Current Bioinformatics Radioimmunotherapy of Solid Tumors: Searching for the Right Target
Current Drug Delivery TNF-Related Apoptosis-Inducing Ligand (TRAIL) as a Pro-Apoptotic Signal Transducer with Cancer Therapeutic Potential
Current Pharmaceutical Design Impact of Traditional Therapies and Biologics on Cardiovascular Diseases in Rheumatoid Arthritis
Current Vascular Pharmacology Prognostic Factors after R0 Resection of Colorectal Cancer Liver Metastases: A Systematic Review and Pooled-Analysis
Reviews on Recent Clinical Trials Review of Childhood Obesity (Balar Athidhoola Rogam) in Traditional Siddha Indian Medicine
Current Traditional Medicine Metabolite Identification in NMR-based Metabolomics
Current Metabolomics Probiotics and the Intestinal Microflora: What Impact on the Immune System, Infections and Aging?
Current Nutrition & Food Science Antibody-Based Imaging of HER-2: Moving into the Clinic
Current Molecular Medicine Phytochemicals - A Novel and Prominent Source of Anti-cancer Drugs Against Colorectal Cancer
Combinatorial Chemistry & High Throughput Screening A Simple and Reliable Approach for Assessing Anticancer Activity In Vitro
Current Medicinal Chemistry Perspectives/Opinion: ADVANCED MEDICAL IMAGING IN THE ERA OF PERSONALIZED OR PRECISION MEDICINE
Current Medical Imaging Evaluation of Antidiabetic Activity of <i>Rosmarinus officinalis var. prostratus</i> Growing in Syria in Alloxan Diabetic Rats
Current Bioactive Compounds Merging Traditional Chinese Medicine with Modern Drug Discovery Technologies to Find Novel Drugs and Functional Foods
Current Drug Discovery Technologies Editorial [Hot Topic: Biomarkers of Chemotherapeutics Efficacy and Toxicity in Colorectal Cancer (Guest Editor: Amalia Azzariti)]
Current Drug Metabolism Endothelial Cell Targeted Molecular Imaging in Tumor Angiogenesis: Strategies and Current Status
Current Pharmaceutical Biotechnology Regulation of MicroRNAs by Phytochemicals: A Promising Strategy for Cancer Chemoprevention
Current Cancer Drug Targets Angiogenesis Inhibition: State of the Art, Forgotten Strategies and New Perspectives in Cancer Therapy
Current Cancer Therapy Reviews Cardiovascular Risk Calculators and their Applicability to South Asians
Current Diabetes Reviews