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.
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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 |
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