HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib

被引:0
作者
Giorgio Valabrega
Sonia Capellero
Giuliana Cavalloni
Gianluca Zaccarello
Annalisa Petrelli
Giorgia Migliardi
Andrea Milani
Caterina Peraldo-Neia
Loretta Gammaitoni
Anna Sapino
Carla Pecchioni
Aldo Moggio
Silvia Giordano
Massimo Aglietta
Filippo Montemurro
机构
[1] University of Turin Medical School,Department of Oncological Sciences, Institute for Cancer Research and Treatment (IRCC)
[2] University of Turin Medical School,Oncological Department, Medical Oncology, Institute for Cancer Research and Treatment (IRCC)
[3] University of Turin Medical School,Laboratory of Immunogenetics, Department of Genetics, Biology, and Biochemistry
[4] University of Turin Medical School,Division of Cancer Biology, IRCC
[5] Laboratory of Cancer Genomics,Department of Biomedical Sciences and Human Oncology
[6] Fondazione Edo ed Elvo Tempia Valenta,undefined
[7] University of Turin Medical School,undefined
来源
Breast Cancer Research and Treatment | 2011年 / 130卷
关键词
HER2; Breast cancer; Resistance; Trastuzumab; Lapatinib; Sorafenib; Mcl-1; Survivin;
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摘要
Trastuzumab has changed the prognosis of HER2 positive breast cancers. Despite this progress, resistance to trastuzumab occurs in most patients. Newer anti-HER2 therapies, like the dual tyrosine-kinase inhibitor (TKI) lapatinib, show significant antitumor activity, indicating that HER2 can be still exploited as a target after trastuzumab failure. However, since a high proportion of patients fail to respond to these alternative strategies, it is possible that cell escape from HER2 targeting may rely on HER2 independent pathways. The knowledge of these pathways deserve to be exploited to develop new therapies. We characterized two human HER2 overexpressing breast cancer cell lines resistant to trastuzumab and lapatinib (T100 and JIMT-1) from a molecular and biological point of view. Indeed, we assessed both in vitro and in vivo the activity of the multitarget inhibitor sorafenib. In both cell lines, the previously proposed mechanisms did not explain resistance to HER2 inhibitors. Notably, silencing HER2 by shRNA did not affect the growth of our cells, suggesting loss of reliance upon HER2. Moreover, we identified alterations in two antiapoptotic proteins Mcl-1 and Survivin which are known to be targets of the multikinase inhibitor sorafenib. Moreover, sorafenib, strongly inhibited the in vitro growth of T100 and JIMT-1 cells, through the downregulation of both Mcl-1 and Survivin. Similar results were obtained in JIMT-1 xenografts subcutaneously injected in NOD SCID mice. We provide preclinical evidence that tumor cells resistant to trastuzumab and lapatinib may rely on HER2 independent pathways that can be efficiently inhibited by sorafenib.
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页码:29 / 40
页数:11
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