Lapatinib in combination with radiation diminishes tumor regrowth in HER2+ and basal-like/EGFR+ breast tumor xenografts.
OBJECTIVE
To determine whether lapatinib, a dual epidermal growth factor receptor (EGFR)/HER2 kinase inhibitor, can radiosensitize EGFR+ or HER2+ breast cancer xenografts.


METHODS
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.


CONCLUSIONS
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.
Sambade
Maria J
MJ
Department of Radiation Oncology, University of North Carolina at Chapel Hill, NC 27599-7295, USA.
Kimple
Randall J
RJ
Camp
J Terese
JT
Peters
Eldon
E
Livasy
Chad A
CA
Sartor
Carolyn I
CI
Shields
Janiel M
JM
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D006801:Humans; D000077341:Lapatinib; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011799:Quinazolines; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous
D066246:ErbB Receptors; D000077341:Lapatinib; D048052:Mitogen-Activated Protein Kinase 3; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D018719:Erb-b2 Receptor Tyrosine Kinases
Int J Radiat Oncol Biol Phys. 2000 Dec 1;48(5):1519-28
11121658
Radiother Oncol. 2009 Dec;93(3):639-44
19853943
Nat Clin Pract Oncol. 2004 Dec;1(2):80-7
16264825
Clin Cancer Res. 2007 Apr 15;13(8):2329-34
17438091
J Clin Oncol. 2005 Feb 20;23(6):1152-60
15718311
Breast Cancer Res Treat. 2006 Feb;95(3):243-55
16261404
Oncogene. 2003 Sep 1;22(37):5855-65
12947392
Breast Cancer Res. 2007;9(5):R61
17875215
Lancet Oncol. 2009 May;10(5):522-7
19410197
Oncogene. 2002 Sep 12;21(41):6255-63
12214266
Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):344-52
14751502
Breast J. 2004 May-Jun;10(3):204-10
15125746
Breast Cancer Res Treat. 2009 Jul;116(2):317-28
18839307
N Engl J Med. 2006 Feb 9;354(6):567-78
16467544
Annu Rev Pharmacol Toxicol. 2004;44:195-217
14744244
Nat Clin Pract Oncol. 2006 Sep;3(9):463
16955079
Curr Opin Cell Biol. 2009 Apr;21(2):177-84
19208461
Cancer Chemother Pharmacol. 2009 Nov;64(6):1139-48
19294387
Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):1163-73
15234052
Ann Oncol. 2009 Jun;20(6):1026-31
19179558
Cancer Res. 2009 Jan 15;69(2):565-72
19147570
J Clin Oncol. 2005 Apr 10;23(11):2502-12
15684311
Lancet Oncol. 2009 Jun;10(6):581-8
19394894
Nat Clin Pract Oncol. 2008 Mar;5(3):149-59
18212769
Radiother Oncol. 2005 Feb;74(2):109-15
15734198
Cancer Metastasis Rev. 2008 Sep;27(3):387-402
18427731
J Natl Cancer Inst. 2008 Aug 6;100(15):1092-103
18664652
Cancer Res. 2000 Apr 15;60(8):2190-6
10786683
J Oncol. 2009;2009:967920
19365583
Clin Cancer Res. 2004 Oct 1;10(19):6487-501
15475436
Semin Radiat Oncol. 2003 Jan;13(1):22-30
12520461
BMC Genomics. 2007 Jul 31;8:258
17663798
J Clin Oncol. 2008 May 20;26(15):2568-81
18487574
Breast Cancer Res Treat. 2008 Dec;112(3):533-43
18188694
N Engl J Med. 2006 Dec 28;355(26):2733-43
17192538
Clin Cancer Res. 2008 Dec 1;14(23):7900-8
19047120
J Clin Oncol. 2008 Mar 1;26(7):1066-72
18212337
Mol Cancer Ther. 2001 Dec;1(2):85-94
12467226
Int J Radiat Oncol Biol Phys. 2010 Mar 15;76(4):998-1004
19560883
Breast Cancer. 2003;10(3):268-74
12955041