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:Cancer Biology and Therapeutics, Kourilsky building 1st floor, Hopital Saint-Antoine, 184 rue du Faubourg Saint-Antoine, Paris 75012, France.
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.
