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- Title
Epidermal growth factor receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models.
- Authors
Formisano, Luigi; Nappi, Lucia; Rosa, Roberta; Marciano, Roberta; D'Amato, Claudia; D'Amato, Valentina; Damiano, Vincenzo; Raimondo, Lucia; Iommelli, Francesca; Scorziello, Antonella; Troncone, Giancarlo; Veneziani, Bianca Maria; Parsons, Sarah J.; De Placido, Sabino; Bianco, Roberto
- Abstract
Introduction Src tyrosine kinase overactivation has been correlated with a poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer. To identify the mechanism by which Src overexpression sustains this resistance, we tested a panel of breast cancer cell lines either sensitive or resistant to lapatinib. Methods To determine the role of Src in lapatinib resistance, we evaluated the effects of Src inhibition/silencing in vitro on survival, migration and invasion of lapatinib-resistant cells. In vivo experiments were performed in JIMT-1 lapatinib-resistant cells orthotopically implanted in nude mice. We used artificial metastasis assays to evaluate the effect of Src inhibition on the invasiveness of lapatinib-resistant cells. Src-dependent signal transduction was investigated with Western blot and ELISA analyses. Results Src activation was higher in lapatinib-resistant than in lapatinib-sensitive cells. The selective small-molecule Src inhibitor saracatinib combined with lapatinib synergistically inhibited the proliferation, migration and invasion of lapatinib-resistant cells. Saracatinib combined with lapatinib significantly prolonged survival of JIMT-1-xenografted mice compared with saracatinib alone, and impaired the formation of lung metastases. Unexpectedly, in lapatinibresistant cells, Src preferentially interacted with epidermal growth factor receptor (EGFR) rather than with HER2. Moreover, EGFR targeting and lapatinib synergistically inhibited survival, migration and invasion of resistant cells thereby counteracting Src-mediated resistance. These findings demonstrate that Src activation in lapatinib-resistant cells depends on EGFR-dependent rather than on HER2-dependent signaling. Conclusions Complete pharmacological EGFR/HER2 inhibition is required to reverse Src-dependent resistance to lapatinib in breast cancer.
- Subjects
EPIDERMAL growth factor receptors regulation; LAPATINIB; BREAST cancer; PROTEIN-tyrosine kinases; ENZYME inhibitors; CELL lines; CELL proliferation; CELLULAR signal transduction
- Publication
Breast Cancer Research, 2014, Vol 18, Issue 3, p1
- ISSN
1465-5411
- Publication type
Article
- DOI
10.1186/bcr3650