orals International Association for Breast Cancer Research 2014

Understanding and targeting acquired ESR1 mutations in hormone resistant breast cancers (#62)

Geoffrey Greene 1 , Sean Fanning 1 , Sarat Chandarlapaty 2 , Weiyi Toy 2 , John Katzenellenbogen 3 , Benita Katzenellenbogen 3 , Christopher Mayne 3 , Yang Shen 4 , Abhishek Sharma 3 , Kendall Nettles 5
  1. University of Chicago, Chicago, IL, USA
  2. Memorial Sloan Kettering Cancer Center, New York, NY, USA
  3. University of Illinois, Urbana, IL, USA
  4. Toyota Institute, Chicago, IL, USA
  5. Scripps Florida, Jupiter, FL, USA

Estrogen receptor alpha (ERα) is a well-established target for the treatment of breast cancer. Approximately 70% of breast cancers express ERa and many of these are sensitive to anti-estrogen or estrogen-deprivation therapies. Tamoxifen, a selective estrogen receptor modulator (SERM), is the drug of choice for early stage disease and aromatase inhibitors (AIs) are used either in place of or sequentially in postmenopausal women. Fulvestrant, a selective estrogen degrader (SERD) is sometimes used in women who fail tamoxifen/AI therapy. Unfortunately, metastatic breast tumors recur in approximately half of patients and become SERM/AI/SERD resistant while remaining ER-positive in many cases. Recently, several somatic mutations in ESR1 were identified in patients who received SERM/AI/SERD therapy for an average of five years. Because these mutations were observed in approximately 25% of tumors and the most frequent mutations (Y537S or D538G) were located in the ligand-binding domain (LBD), they represent a likely mechanism for acquired SERM/AI/SERD insensitivity. Further studies showed that these mutations confer hormone-independent ERα activity and that the inhibitory activity of tamoxifen and fulvestrant is significantly reduced. X-ray crystallography and molecular dynamics simulations, coupled with biochemical assays and in vitro and in vivo ER+ breast cancer cell studies have been used to dissect the role of these somatic mutation in acquired SERM/AI/SERD resistance. X-ray crystal structures of the D538G mutant in the unliganded (apo), agonist and SERM-bound states, combined with molecular dynamics simulations, reveal a stabilized loop between H11 and H12 that favors an agonist conformation versus an antagonist conformation. Biochemical and breast cancer cell studies further reveal functional insights that help explain mutant ERα function within these tumors. This information is also being used to identify, design and assess the utility of next generation SERMs and SERDs that will be clinically effective in treating mutant ER+, therapy-resistant breast cancer.