Benefits of HER2-targeted therapy in HER2+ cancers are limited due to significant de novo and acquired resistance, and no therapy options exist for patients with refractory disease. Exploiting oncogene-induced vulnerabilities as a therapeutic strategy in cancers has emerged as a promising alternative to targeting of driver oncogenes. Our preliminary in silico analyses of clinical datasets and in vitro analyses on cell lines have revealed that HER2 overexpression in the mammary epithelial cells induces proteotoxic stress in the endoplasmic reticulum (ER), which is relieved in HER2+ breast cancer cells due to specific overexpression of the ER-associated degradation (ERAD) complex. We have found that HER2+ breast cancer cells are acutely dependent on ERAD to maintain proper protein homeostasis and survival. Accordingly, targeting of ERAD induces proteotoxic ER stress and cell death selectively in EGFR/HER2+ breast cancer cells, including those with de novo and acquired resistance to trastuzumab and lapatinib. In addition, we have found that combinatorial targeting of ERAD and adaptive ER stress response machinery can synergize in the induction of proteotoxic ER stress and cell death in drug- resistant HER2+ cells. Based on these results, we propose that oncogenic HER2-induced proteotoxic ER stress is a clinically significant vulnerability, and that the therapeutic targeting strategies to force irrecoverable proteotoxic ER stress are an effective approach against therapy-refractory HER2+ breast cancers. In this proposal, we propose to 1) identify the mechanisms of addiction of HER2+ cells to ERAD, 2) identify novel potent combinatorial strategies of maximizing oncogenic ER stress, and 3) test in vivo efficacy of inducing oncogenic proteotoxic stress in drug-resistant breast cancers.
In Aim 3, we will test several novel inhibitors of ERAD in in vivo tumor growth assays in mice making use of patient- derived xenograft lines.

Public Health Relevance

Standard-of-care targeted therapy for metastatic HER2+ breast cancers are not desirably effective due to substantial resistance of tumors to these drugs. In this proposal, we will investigate the efficacy of a therapeutic strategy that, based on our preliminary analyses, is equally effective on therapy-sensitive and resistant HER2+ breast cancers. Therefore, this proposal carries high public health relevance due to its potential to suggest novel and effective treatments for therapy-refractory HER2+ breast cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA193549-02
Application #
9061645
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Salnikow, Konstantin
Project Start
2015-05-01
Project End
2020-04-30
Budget Start
2016-05-01
Budget End
2017-04-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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