Epidermal growth factor-receptor activation modulates Src-dependent resistance to lapatinib in breast cancer models

被引：56

作者：

Formisano, Luigi ^{[1
,2
]}

Nappi, Lucia ^{[1
,2
]}

Rosa, Roberta ^{[1
,2
]}

Marciano, Roberta ^{[1
,2
]}

D'Amato, Claudia ^{[1
,2
]}

D'Amato, Valentina ^{[1
,2
]}

Damiano, Vincenzo ^{[1
,2
]}

Raimondo, Lucia ^{[1
,2
]}

Iommelli, Francesca ^{[3
]}

Scorziello, Antonella ^{[4
]}

Troncone, Giancarlo ^{[4
]}

Veneziani, Bianca Maria ^{[4
]}

Parsons, Sarah J. ^{[5
]}

De Placido, Sabino ^{[1
,2
]}

Bianco, Roberto ^{[1
,2
]}

机构：

[1] Univ Naples Federico II, Dept Clin Med, I-80131 Naples, Italy

[2] Univ Naples Federico II, Dept Chirurg, I-80131 Naples, Italy

[3] CNR, Ist Biostrutture & Bioimmagini, I-80131 Naples, Italy

[4] Univ Naples Federico II, I-80131 Naples, Italy

[5] Univ Virginia Hlth Syst, Ctr Canc, Dept Microbiol Immunol & Canc Biol, Charlottesville, VA 22908 USA

来源：

BREAST CANCER RESEARCH | 2014年 / 16卷 / 03期

关键词：

TYROSINE KINASE INHIBITOR; ACQUIRED-RESISTANCE; FAMILY KINASES; ANTITUMOR-ACTIVITY; EPITHELIAL-CELLS; ZD1839; IRESSA; IN-VITRO; HER2; TRASTUZUMAB; PHOSPHORYLATION;

D O I：

10.1186/bcr3650

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 lapatinib-resistant 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 pharmacologic EGFR/HER2 inhibition is required to reverse Src-dependent resistance to lapatinib in breast cancer.

引用

页数：15

共 47 条

[1] Src family kinases and HER2 interactions in human breast cancer cell growth and survival [J].