NOXA Loss as a Major Mechanism of Intrinsic Resistance to Targeted Therapies in Breast Cancer
Abstract
We continue to make significant and timely progress for this latest period. Our grant hypothesis was that MCL-1 inhibition can sensitize HER2 inhibitors in HER2 amplified breast cancer and ER inhibitors in ER breast cancer. Highlights of the past 12 months include data supporting the use of the novel HER2 inhibitor, tucatinib, in combination with dinaciclib both in vitro and in mouse models of HER2 amplified breast cancer. We have uncovered a feedback activation of PI3K and MEK signaling from dinaciclib, which is abrogated by HER2 inhibitors in HER2 amplified breast cancer, adding a second layer of rationale to use these two classes of drugs together. In addition, we have found expression of other anti-apoptotic BCL-2 members other than MCL-1 do not impact the sensitivity of HER2 inhibitors and MCL-1 inhibitors, consistent with a dominant role of the NOXA-MCL-1 axis in sensitivity of HER2 inhibitors in HER2 amplified breast cancer. In ER breast cancer, we have characterized theBCL-2 protein complex changes that underline sensitivity of ER inhibitors plus MCL-1 inhibition through a series of immunoprecipitation experiments. For staining of breast cancer samples, we have rigorously validated a NOXA antibody that we will move forward with.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2020
- Accession Number
- AD1125517
Entities
People
- Anthony Faber
- Maurizio Scaltriti
Organizations
- Memorial Sloan Kettering Cancer Center
- Virginia Commonwealth University