Breast cancer is the second-leading cause of cancer death among American women (1). Approximately 25% of breast cancers overexpress the receptor tyrosine kinase (RTK) protein HER2, which induces cancer cell growth and survival (2). To combat HER2-positive breast cancer, researchers have developed therapies which inhibit HER2 functions, such as lapatinib. Response rates to lapatinib monotherapy are as high as 24% in previously untreated patients (3). Unfortunately, however, drug resistance develops in many patients who initially respond to lapatinib, and most patients do not show initial response. The mechanisms of this resistance are incompletely understood. Therefore, our objectives are to determine (a) the mechanism(s) of lapatinib resistance and (b) a therapeutic means to overcome it. By determining the mechanism of lapatinib resistance we will be empowered to provide additional treatment options for women with lapatinib-resistant breast cancer, for whom effective treatment options are lacking. To determine the mechanism of lapatinib resistance, we have developed a model of acquired lapatinib resistance by treating a HER2-positive breast cancer cell line with lapatinib for longer than 6 months ("LapR" cells), during which the cells became drug-resistant. This resistance is dependent on activation of PI3K through a novel mechanism.
Our specific aims are to: (1) elucidate the mechanism of PI3K activation in these cells, (2) determine whether this mechanism is also involved in primary lapatinib resistance, in addition to acquired resistance, (3) devise a therapeutic strategy to overcome lapatinib resistance, and (4) determine whether the mechanism we have identified predicts patient outcomes.
Aims 1, 2, and 3 will be achieved using biochemical, molecular, and cellular studies of in vitro cultures of cancer cell lines and mouse tumors.
Aim 4 will be performed using patient data. These efforts will increase our knowledge about how some cancer cells escape lapatinib-induced death and how to eliminate such cells therapeutically, which may have significant impact on patients with HER2- positive breast cancer.

Public Health Relevance

This project has the potential to aid the 25% of breast cancer patients who are candidates for treatment with the anti-cancer drug lapatinib (1, 2) to have more successful treatment outcomes. By revealing why tumors are or become lapatinib-resistant, we will be empowered to know what additional therapies are needed to maximize lapatinib effectiveness and thus extend the survival of breast cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31CA165819-02
Application #
8554754
Study Section
Special Emphasis Panel (ZRG1-F09-A (08))
Program Officer
Schmidt, Michael K
Project Start
2012-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2013
Total Cost
$28,584
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030