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Title: Lapatinib in Combination With Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts

Abstract

Purpose: To determine whether lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 kinase inhibitor, can radiosensitize EGFR+ or HER2+ breast cancer xenografts. Methods and Materials: Mice bearing xenografts of basal-like/EGFR+ SUM149 and HER2+ SUM225 breast cancer cells were treated with lapatinib and fractionated radiotherapy and tumor growth inhibition correlated with alterations in ERK1 and AKT activation by immunohistochemistry. Results: Basal-like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib plus radiotherapy, exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.20 during the study period. In contrast, HER2+ SUM225 breast cancer tumors were highly responsive to treatment with lapatinib alone and yielded a relatively lower enhancement ratio average of 1.25 during the study period with lapatinib plus radiotherapy. Durable tumor control in the HER2+ SUM225 model was more effective with the combination treatment than either lapatinib or radiotherapy alone. Immunohistochemical analyses demonstrated that radiosensitization by lapatinib correlated with ERK1/2 inhibition in the EGFR+ SUM149 model and with AKT inhibition in the HER2+ SUM225 model. Conclusion: Our data suggest that lapatinib combined with fractionated radiotherapy may be useful against EGFR+ and HER2+ breast cancers and thatmore » inhibition of downstream signaling to ERK1/2 and AKT correlates with sensitization in EGFR+ and HER2+ cells, respectively.« less

Authors:
; ; ;  [1];  [2];  [1]
  1. Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, NC (United States)
  2. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC (United States)
Publication Date:
OSTI Identifier:
21372311
Resource Type:
Journal Article
Journal Name:
International Journal of Radiation Oncology, Biology and Physics
Additional Journal Information:
Journal Volume: 77; Journal Issue: 2; Other Information: DOI: 10.1016/j.ijrobp.2009.12.063; PII: S0360-3016(10)00013-1; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Journal ID: ISSN 0360-3016
Country of Publication:
United States
Language:
English
Subject:
62 RADIOLOGY AND NUCLEAR MEDICINE; EPIDERMIS; FRACTIONATED IRRADIATION; GROWTH FACTORS; INHIBITION; MAMMARY GLANDS; MICE; NEOPLASMS; RADIOTHERAPY; RECEPTORS; TUMOR CELLS; ANIMAL CELLS; ANIMAL TISSUES; ANIMALS; BODY; DISEASES; EPITHELIUM; GLANDS; IRRADIATION; MAMMALS; MEDICINE; MEMBRANE PROTEINS; MITOGENS; NUCLEAR MEDICINE; ORGANIC COMPOUNDS; ORGANS; PROTEINS; RADIOLOGY; RODENTS; SKIN; THERAPY; VERTEBRATES

Citation Formats

Sambade, Maria J, Kimple, Randall J, Camp, J Terese, Peters, Eldon, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, Livasy, Chad A, Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, Sartor, Carolyn I, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, Shields, Janiel M., E-mail: shieldsj@med.unc.ed, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, and Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC. Lapatinib in Combination With Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts. United States: N. p., 2010. Web. doi:10.1016/j.ijrobp.2009.12.063.
Sambade, Maria J, Kimple, Randall J, Camp, J Terese, Peters, Eldon, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, Livasy, Chad A, Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, Sartor, Carolyn I, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, Shields, Janiel M., E-mail: shieldsj@med.unc.ed, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, & Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC. Lapatinib in Combination With Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts. United States. https://doi.org/10.1016/j.ijrobp.2009.12.063
Sambade, Maria J, Kimple, Randall J, Camp, J Terese, Peters, Eldon, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, Livasy, Chad A, Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC, Sartor, Carolyn I, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, Shields, Janiel M., E-mail: shieldsj@med.unc.ed, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, and Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC. 2010. "Lapatinib in Combination With Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts". United States. https://doi.org/10.1016/j.ijrobp.2009.12.063.
@article{osti_21372311,
title = {Lapatinib in Combination With Radiation Diminishes Tumor Regrowth in HER2+ and Basal-Like/EGFR+ Breast Tumor Xenografts},
author = {Sambade, Maria J and Kimple, Randall J and Camp, J Terese and Peters, Eldon and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC and Livasy, Chad A and Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC and Sartor, Carolyn I and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC and Shields, Janiel M., E-mail: shieldsj@med.unc.ed and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC and Department of Dermatology, University of North Carolina at Chapel Hill, Chapel Hill, NC},
abstractNote = {Purpose: To determine whether lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 kinase inhibitor, can radiosensitize EGFR+ or HER2+ breast cancer xenografts. Methods and Materials: Mice bearing xenografts of basal-like/EGFR+ SUM149 and HER2+ SUM225 breast cancer cells were treated with lapatinib and fractionated radiotherapy and tumor growth inhibition correlated with alterations in ERK1 and AKT activation by immunohistochemistry. Results: Basal-like/EGFR+ SUM149 breast cancer tumors were completely resistant to treatment with lapatinib alone but highly growth impaired with lapatinib plus radiotherapy, exhibiting an enhancement ratio average of 2.75 and a fractional tumor product ratio average of 2.20 during the study period. In contrast, HER2+ SUM225 breast cancer tumors were highly responsive to treatment with lapatinib alone and yielded a relatively lower enhancement ratio average of 1.25 during the study period with lapatinib plus radiotherapy. Durable tumor control in the HER2+ SUM225 model was more effective with the combination treatment than either lapatinib or radiotherapy alone. Immunohistochemical analyses demonstrated that radiosensitization by lapatinib correlated with ERK1/2 inhibition in the EGFR+ SUM149 model and with AKT inhibition in the HER2+ SUM225 model. Conclusion: Our data suggest that lapatinib combined with fractionated radiotherapy may be useful against EGFR+ and HER2+ breast cancers and that inhibition of downstream signaling to ERK1/2 and AKT correlates with sensitization in EGFR+ and HER2+ cells, respectively.},
doi = {10.1016/j.ijrobp.2009.12.063},
url = {https://www.osti.gov/biblio/21372311}, journal = {International Journal of Radiation Oncology, Biology and Physics},
issn = {0360-3016},
number = 2,
volume = 77,
place = {United States},
year = {Tue Jun 01 00:00:00 EDT 2010},
month = {Tue Jun 01 00:00:00 EDT 2010}
}