Targeting ESR1-Mutant Breast Cancer
Annual technical rept. 1 Sep 2014 - 31 Aug 2015
SLOAN-KETTERING INST FOR CANCER RESEARCH NEW YORK
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The hypothesis of this proposal is that LBD mutations in ESR1 promote resistance to current FDA approved hormonal therapies and that more potent, selective estrogen receptor degraders SERDs will enable complete inhibition of mutant ER signaling and thus have substantial therapeutic benefit. Our first aim in this proposal was to determine the biochemical and biologic impact of ER mutations found in breast cancer using both structural and cell based assays. We have now have evidence for the effects of the most recurrent mutations, D538G and Y537S inducing an agonist apo-ER structure and promoting estrogen independent tumor growth as well as preliminary evidence for the mutants promoting transcriptional effects including but also beyond those induced by estrogen. Additional aims were to understand how mutant ER is impacted by SERD compounds again using structural, cell-based, and mouse models as readouts. We have evidence that the Y537S and D538G alterations modify the SERM 4OHT induced antagonist structure to a greater extent than SERDs bazedoxifene, suggesting SERDs as potentially superior agents. Our biologic data from a suite of ER antagonists suggest the same, that SERDs such as bazedoxifene or GDC0180 potently inhibit wild type and mutant ER driven phenotypes. Overall, the work is suggesting rational steps forward towards targeting ER mutant driven cancers.
- Medicine and Medical Research