NOXA Loss as a Major Mechanism of Intrinsic Resistance to Targeted Therapies in Breast Cancer
Abstract
We hypothesized that MCL-1 inhibition could sensitize HER2 amplified breast cancer to HER2 inhibitors and ER-positive breast cancer to ER inhibitors. We have provided preclinical evidence to support the use of ER inhibitors in combination with MCL-1inhibitors in ER-positive breast cancer. In addition, our findings have qualified the novel miRNA4728-NOXA-MCL1 axis as a key determinant of sensitivity to HER2 inhibitors in HER2 amplified breast cancers and ER inhibitors in ER-positive breast cancer. In addition, treatment with HER2 inhibitors or ER inhibitors leads to NOXA loss, which results in MCL-1 addiction. NOXA-high and MCL1-low ER-positive/HER2-negative breast cancers were associated with shorter recurrence free survival. Given these findings and the success of anti-HER2 antibody drug conjugates in HER2-amplified (HER2-positive) breast cancer, during the past 12 months we have deprioritized the study of HER2-positive disease and focused on ER-positive/HER2-negative breast cancers, expanding our analyses to additional ER-positive/HER2-negative breast cancer cohorts. Using immunohistochemical and omics studies, we have found a higher extent of tumor infiltrating lymphocytes and tumor mutational burden in NOXA-high and MCL-1-high ER-positive/HER2-negative breast cancers, as well as an enrichment in pathogenic genetic alterations affectingWHSC1L1, BAP1 and PRKAR1A in NOXA-high ER-positive/HER2-negative breast cancer samples as compared to NOXA-low samples.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jan 01, 2023
- Accession Number
- AD1210244
Entities
People
- Jorge S Reis-Filho
Organizations
- Memorial Sloan Kettering Cancer Center
- VCU Medical Center