Modeling and Targeting of Oncogenic Liability in Drug-Resistant Breast Cancer
Abstract
Amplification or overexpression of the ERBB2 gene occurs in approximately 15%-30% of breast cancers and correlates with poor prognosis and recurrence. Although multiple potent drugs have been developed against the HER2 oncogene in the clinic, their effect is usually short-lived due to acquired resistance, and still many patients do not respond to these drugs at all. In order to find more effective therapeutic strategies to combat drug-resistant tumors, we considered an alternative approach to targeting of the driver oncogene: exploiting oncogenic stress. By using a state-of-the-art integrated approach, we have uncovered a novel vulnerability of HER2+ breast cancers, called oncogene-induced ER stress. Specifically, activation of HER2 in breast cancers triggers a significant stress in cells, which normally blocks cancer progression. However, cancer cells activate adaptive molecular machinery to relieve this stress and therefore promote tumor growth. We have found that inhibiting these adaptive molecular machineries can reactivate oncogene-induced stress and kill oncogene-transformed tumor cells. Importantly, this strategy is highly potent on drug-resistant HER2+ breast cancer cells. 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. The proposed work, if successful, will shed light on the molecular mechanisms of oncogene-induced stress and reveal the efficacy of exploiting oncogene-induced stress for the therapy of metastatic HER2+ breast cancers that have progressed on HER2-targeted therapy. These research projects and the research environment in Komurov lab, Children s Hospital and the University of Cincinnati are highly complementary of the Principal Investigator s (PI s) career goals of becoming a breast cancer systems biologist. The PI will be immersed in a highly collaborative and interdisciplinary environment in Komurov lab and our multiple collaborators, allowing him to attain the skills to conduct independent research in breast cancer biology and lead interdisciplinary research projects.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1610028
Entities
People
- Navneet Singh
Organizations
- United States Army