Breast cancer cells with acquired resistance to the EGFR tyrosine kinase inhibitor gefitinib show persistent activation of MAPK signaling |
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Authors: | Nicola Normanno Manuela Campiglio Monica R Maiello Antonella De Luca Mario Mancino Marianna Gallo Amelia D’Alessio Sylvie Menard |
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Institution: | (1) Cell Biology and Preclinical Models Unit, INT-Fondazione Pascale, 80131 Naples, Italy;(2) Centro di Ricerche Oncologiche di Mercogliano (CROM), 83013 Mercogliano, AV, Italy;(3) Molecular Targeting Unit, Istituto Tumori Milano, 20133 Milan, Italy |
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Abstract: | Although the epidermal growth factor receptor (EGFR) is frequently expressed in human primary breast carcinoma, the majority
of breast cancer patients do not respond to treatment with EGFR tyrosine-kinase inhibitors such as gefitinib. We isolated
through a stepwise dose escalation of the drug two gefitinib-resistant SK-Br-3 clones, ZD6 and ZD10 (ZD) cells, which showed,
respectively, a three- to five-fold increase in the IC50 for gefitinib as compared with parental cells. The levels of expression of EGFR were increased in ZD cells as compared with
wild-type SK-Br-3 cells. The phosphorylation of EGFR, ErbB-2, ErbB-3 and Akt was significantly reduced in gefitinib-resistant
cells. In contrast, ZD cells showed levels of MAPK phosphorylation similar to untreated wild-type cells when cultured in presence
of gefitinib. Persistent activation of MAPK was also observed in gefitinib-resistant clones isolated from MDA-MB-175 and MDA-MB-361
breast cancer cell lines. ZD cells showed an increased sensitivity to the MEK inhibitor PD98059 as compared with SK-Br-3 cells,
and a synergistic anti-tumor effect was observed when ZD cells were treated with a combination of gefitinib and PD98059. Overexpression
of a constitutively activated form of p42-MAPK in SK-Br-3 cells resulted in an approximately 50% increase in the IC50 to gefitinib. Finally, culture of ZD10 resistant cells in absence of gefitinib led to reversion of the resistant phenotype.
These observations suggest that MAPK signaling might play a role in the resistance that develops in breast cancer cells after
long-term exposure to gefitinib.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
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Keywords: | Breast cancer EGFR Tyrosine kinase inhibitors Drug resistance MAPK |
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