Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / pharmacology*
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Antibodies, Monoclonal, Humanized / therapeutic use
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Antineoplastic Agents / pharmacology*
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Antineoplastic Agents / therapeutic use
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Benzenesulfonates / pharmacology*
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Benzenesulfonates / therapeutic use
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Breast Neoplasms / metabolism*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm / genetics
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Female
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism
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Lapatinib
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Mice
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Mice, Inbred NOD
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Mice, SCID
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Mitogen-Activated Protein Kinases / metabolism
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Myeloid Cell Leukemia Sequence 1 Protein
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Niacinamide / analogs & derivatives
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Oncogene Protein v-akt / metabolism
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Phenylurea Compounds
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Pyridines / pharmacology*
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Pyridines / therapeutic use
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Quinazolines / pharmacology*
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Quinazolines / therapeutic use
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RNA, Small Interfering
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / genetics
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Signal Transduction / drug effects
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Sorafenib
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Survivin
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Trastuzumab
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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BIRC5 protein, human
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Benzenesulfonates
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Inhibitor of Apoptosis Proteins
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Mcl1 protein, mouse
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Myeloid Cell Leukemia Sequence 1 Protein
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Phenylurea Compounds
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-bcl-2
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Pyridines
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Quinazolines
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RNA, Small Interfering
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Survivin
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Lapatinib
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Niacinamide
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Sorafenib
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Phosphatidylinositol 3-Kinases
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Receptor, ErbB-2
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Oncogene Protein v-akt
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Mitogen-Activated Protein Kinases
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Trastuzumab