title: HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib.
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.
authors.affiliation: Department of Oncological Sciences, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo, TO, Italy. giorgio.valabrega@unito.it
authors.forename: Giorgio
authors.initials: G
authors.lastname: Valabrega
authors.forename: Sonia
authors.initials: S
authors.lastname: Capellero
authors.forename: Giuliana
authors.initials: G
authors.lastname: Cavalloni
authors.forename: Gianluca
authors.initials: G
authors.lastname: Zaccarello
authors.forename: Annalisa
authors.initials: A
authors.lastname: Petrelli
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.forename: Andrea
authors.initials: A
authors.lastname: Milani
authors.forename: Caterina
authors.initials: C
authors.lastname: Peraldo-Neia
authors.forename: Loretta
authors.initials: L
authors.lastname: Gammaitoni
authors.forename: Anna
authors.initials: A
authors.lastname: Sapino
authors.forename: Carla
authors.initials: C
authors.lastname: Pecchioni
authors.forename: Aldo
authors.initials: A
authors.lastname: Moggio
authors.forename: Silvia
authors.initials: S
authors.lastname: Giordano
authors.forename: Massimo
authors.initials: M
authors.lastname: Aglietta
authors.forename: Filippo
authors.initials: F
authors.lastname: Montemurro
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics / Q000378:metabolism; D000077341:Lapatinib; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide / Q000031:analogs & derivatives; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D000077022:Survivin; D000068878:Trastuzumab; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D051034:Inhibitor of Apoptosis Proteins; D000077341:Lapatinib; D020928:Mitogen-Activated Protein Kinases; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009536:Niacinamide; D051058:Oncogene Protein v-akt; D010671:Phenylurea Compounds; D019869:Phosphatidylinositol 3-Kinases; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D011799:Quinazolines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077157:Sorafenib; D000077022:Survivin; D000068878:Trastuzumab; C107489:BIRC5 protein, human; C579094:Mcl1 protein, mouse