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.