Amplification of the HER2 (ERBB2) gene occurs in approximately 25% of breast cancers and is associated with poor patient outcome. The antibody trastuzumab and the tyrosine kinase inhibitor lapatinib are the two approved drugs by the FDA for the treatment of HER2-positive breast cancer. Although clinically effective, many patients with HER2 gene-amplified breast cancer either do not respond or eventually escape trastuzumab and lapatinib, suggesting the presence of de novo and acquired mechanisms of drug resistance. In addition, molecular alterations involving the phosphatidylinositol-3 kinase (PI3K) signaling pathway are arguably the most frequent in breast cancer, encompassing together over 30% of invasive mammary tumors. In many cases, these alterations coexist with HER2 gene amplification and potentially mediate resistance to HER2 antagonists. We propose that, as a result of selective pressure by trastuzumab and/or lapatinib, breast cancers 1) upregulate compensatory survival signaling pathways which, in some cases, may be 'targetable'with an existing drug or combination of drugs, 2) utilize the PI3K/Akt pathway is a predominant mechanism of escape from anti-HER2 drugs which can be eliminated by concomitant use of PI3K inhibitors, and 3) 'acquire'or are enriched for mutations in the HER2 gene which may be present in a fraction of the HER2 alleles in tumors with HER2 gene amplification. To test these hypotheses, we propose the following specific aims:
Aim 1. To determine the mechanism(s) by which mutations in PI3K enhance HER2-mediated transformation in human mammary epithelial cells.
Aim 2. To determine whether genetic and/or pharmacological inhibitors of PI3K reverse resistance to HER2 inhibitors in HER2-overexpresing breast cancer cells with PIK3CA mutations.
Aim 3. To determine molecular mechanisms of acquired resistance to the HER2 tyrosine kinase inhibitor lapatinib in HER2-overexpressing human breast cancer cells.

Public Health Relevance

Amplification of the HER2 gene occurs in approximately 25% of breast cancers and is associated with poor patient outcome. The antibody trastuzumab and the tyrosine kinase inhibitor lapatinib are the two FDA- approved drugs for the treatment of HER2+ breast cancer but many patients either do not respond or eventually escape these drugs. The research proposed in this application aims at discovering those mechanisms or resistance to anti-HER2 drugs which, in turn, will contribute to the eventual elimination of HER2+ breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA080195-13
Application #
8433480
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
1999-01-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
13
Fiscal Year
2013
Total Cost
$293,808
Indirect Cost
$105,470
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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Arteaga, Carlos L; Engelman, Jeffrey A (2014) ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell 25:282-303
Balko, Justin M; Stricker, Thomas P; Arteaga, Carlos L (2013) The genomic map of breast cancer: which roads lead to better targeted therapies? Breast Cancer Res 15:209
Garner, Andrew P; Bialucha, Carl U; Sprague, Elizabeth R et al. (2013) An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res 73:6024-35
Rexer, Brent N; Ghosh, Ritwik; Narasanna, Archana et al. (2013) Human breast cancer cells harboring a gatekeeper T798M mutation in HER2 overexpress EGFR ligands and are sensitive to dual inhibition of EGFR and HER2. Clin Cancer Res 19:5390-401
Rexer, Brent N; Arteaga, Carlos L (2013) Optimal targeting of HER2-PI3K signaling in breast cancer: mechanistic insights and clinical implications. Cancer Res 73:3817-20
Hanker, Ariella B; Cook, Rebecca S; Arteaga, Carlos L (2013) Mouse models and anti-HER2 therapies. Oncotarget 4:1866-7
Hanker, Ariella B; Pfefferle, Adam D; Balko, Justin M et al. (2013) Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci U S A 110:14372-7
Morrison, Meghan M; Hutchinson, Katherine; Williams, Michelle M et al. (2013) ErbB3 downregulation enhances luminal breast tumor response to antiestrogens. J Clin Invest 123:4329-43
Garrett, Joan T; Sutton, Cammie R; Kuba, Maria Gabriela et al. (2013) Dual blockade of HER2 in HER2-overexpressing tumor cells does not completely eliminate HER3 function. Clin Cancer Res 19:610-9

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