NOXA Loss as a Major Mechanism of Intrinsic Resistance to Targeted Therapies in Breast Cancer
Abstract
Targeted therapies have altered standard patient care dramatically in a number of different cancers over the past 10 years. In breast cancer, HER2 inhibitors (HER2i) are now a main component of treating HER2-amplified breast cancers, and patients with local disease as well as those with advanced disease have benefited from the addition of these inhibitors. Despite the obvious successes of HER2i, these drugs are not as efficient as other targeted therapies in other cancers, such as EGFR inhibitors in EGFR mutant lung cancer and BRAF inhibitors in BRAF mutant melanoma. As such, HER2-amplified breast cancer remains one of the most difficult to treat and aggressive breast cancer subtypes. The factors underscoring this relative resistance to HER2i in HER2-amplified breast cancers remain underexplored and are the topic of this proposal. We have identified a deficient cell death response, or "apoptotic block," following HER2i treatment as underlying intrinsic resistance to HER2i in HER2-amplified breast cancer. Mechanistically, we have found that, remarkably, a gene that gets co-amplified (increased) with HER2 in HER2-amplified breast cancer actually causes this apoptotic block to HER2i by blocking a protein called the Estrogen receptor, which, in turn, fails to upregulate the pro-death protein NOXA. The result is remarkably low levels of NOXA, which leaves the survival-promoting protein MCL-1 unblocked, preventing cell death following HER2i treatment and, as such, resistance to therapy. Importantly, addition of a pharmaceutical inhibitor of MCL-1 sensitizes HER2-amplified breast cancers to HER2i. This grant is aimed at further characterizing the combination of MCL-1i and HER2i and to test the ability of the combination in multiple mouse models to shrink tumors in order to set the stage for clinical trials of this novel, rational, and potent targeted therapy combination (beyond the scope of this grant).
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810562
Entities
People
- Maurizio Scaltriti
Organizations
- Memorial Sloan Kettering Cancer Center
- United States Army