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HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib.
Breast Cancer Res Treat. 2011 Nov; 130(1):29-40.BC

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+Show Affiliations

Department of Oncological Sciences, Institute for Cancer Research and Treatment (IRCC), University of Turin Medical School, Candiolo, TO, Italy. giorgio.valabrega@unito.itNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21153051

Citation

Valabrega, Giorgio, et al. "HER2-positive Breast Cancer Cells Resistant to Trastuzumab and Lapatinib Lose Reliance Upon HER2 and Are Sensitive to the Multitargeted Kinase Inhibitor Sorafenib." Breast Cancer Research and Treatment, vol. 130, no. 1, 2011, pp. 29-40.
Valabrega G, Capellero S, Cavalloni G, et al. HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib. Breast Cancer Res Treat. 2011;130(1):29-40.
Valabrega, G., Capellero, S., Cavalloni, G., Zaccarello, G., Petrelli, A., Migliardi, G., Milani, A., Peraldo-Neia, C., Gammaitoni, L., Sapino, A., Pecchioni, C., Moggio, A., Giordano, S., Aglietta, M., & Montemurro, F. (2011). HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib. Breast Cancer Research and Treatment, 130(1), 29-40. https://doi.org/10.1007/s10549-010-1281-5
Valabrega G, et al. HER2-positive Breast Cancer Cells Resistant to Trastuzumab and Lapatinib Lose Reliance Upon HER2 and Are Sensitive to the Multitargeted Kinase Inhibitor Sorafenib. Breast Cancer Res Treat. 2011;130(1):29-40. PubMed PMID: 21153051.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - HER2-positive breast cancer cells resistant to trastuzumab and lapatinib lose reliance upon HER2 and are sensitive to the multitargeted kinase inhibitor sorafenib. AU - Valabrega,Giorgio, AU - Capellero,Sonia, AU - Cavalloni,Giuliana, AU - Zaccarello,Gianluca, AU - Petrelli,Annalisa, AU - Migliardi,Giorgia, AU - Milani,Andrea, AU - Peraldo-Neia,Caterina, AU - Gammaitoni,Loretta, AU - Sapino,Anna, AU - Pecchioni,Carla, AU - Moggio,Aldo, AU - Giordano,Silvia, AU - Aglietta,Massimo, AU - Montemurro,Filippo, Y1 - 2010/12/09/ PY - 2010/04/30/received PY - 2010/11/23/accepted PY - 2010/12/15/entrez PY - 2010/12/15/pubmed PY - 2012/9/15/medline SP - 29 EP - 40 JF - Breast cancer research and treatment JO - Breast Cancer Res Treat VL - 130 IS - 1 N2 - 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. SN - 1573-7217 UR - https://www.unboundmedicine.com/medline/citation/21153051/HER2_positive_breast_cancer_cells_resistant_to_trastuzumab_and_lapatinib_lose_reliance_upon_HER2_and_are_sensitive_to_the_multitargeted_kinase_inhibitor_sorafenib_ DB - PRIME DP - Unbound Medicine ER -