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 #
5R01CA080195-14
Application #
8607133
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
2014-03-19
Budget End
2015-01-31
Support Year
14
Fiscal Year
2014
Total Cost
$303,185
Indirect Cost
$108,836
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
Hyman, David M; Piha-Paul, Sarina A; Won, Helen et al. (2018) HER kinase inhibition in patients with HER2- and HER3-mutant cancers. Nature 554:189-194
Hanker, Ariella B; Brewer, Monica Red; Sheehan, Jonathan H et al. (2017) An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer. Cancer Discov 7:575-585
Hanker, Ariella B; Estrada, Mónica Valeria; Bianchini, Giampaolo et al. (2017) Extracellular Matrix/Integrin Signaling Promotes Resistance to Combined Inhibition of HER2 and PI3K in HER2+ Breast Cancer. Cancer Res 77:3280-3292
Hanker, Ariella B; Garrett, Joan T; Estrada, Mónica Valeria et al. (2017) HER2-Overexpressing Breast Cancers Amplify FGFR Signaling upon Acquisition of Resistance to Dual Therapeutic Blockade of HER2. Clin Cancer Res 23:4323-4334
Whisenant, Jennifer G; McIntyre, J Oliver; Peterson, Todd E et al. (2015) Utility of [18?F]FLT-PET to assess treatment response in trastuzumab-resistant and trastuzumab-sensitive HER2-overexpressing human breast cancer xenografts. Mol Imaging Biol 17:119-28
Zabransky, Daniel J; Yankaskas, Christopher L; Cochran, Rory L et al. (2015) HER2 missense mutations have distinct effects on oncogenic signaling and migration. Proc Natl Acad Sci U S A 112:E6205-14
Young, Christian D; Arteaga, Carlos L; Cook, Rebecca S (2015) Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers. Breast Cancer Res 17:148
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
Whisenant, Jennifer G; Sorace, Anna G; McIntyre, J Oliver et al. (2014) Evaluating treatment response using DW-MRI and DCE-MRI in trastuzumab responsive and resistant HER2-overexpressing human breast cancer xenografts. Transl Oncol 7:768-79
Rexer, Brent N; Arteaga, Carlos L (2014) Outsmarting cancer: the power of hybrid genomic/proteomic biomarkers to predict drug response. Breast Cancer Res 16:303

Showing the most recent 10 out of 109 publications