title: HSP90 empowers evolution of resistance to hormonal therapy in human breast cancer models.
abstract: The efficacy of hormonal therapies for advanced estrogen receptor-positive breast cancers is limited by the nearly inevitable development of acquired resistance. Efforts to block the emergence of resistance have met with limited success, largely because the mechanisms underlying it are so varied and complex. Here, we investigate a new strategy aimed at the very processes by which cancers evolve resistance. From yeast to vertebrates, heat shock protein 90 (HSP90) plays a unique role among molecular chaperones by promoting the evolution of heritable new traits. It does so by regulating the folding of a diverse portfolio of metastable client proteins, many of which mediate adaptive responses that allow organisms to adapt and thrive in the face of diverse challenges, including those posed by drugs. Guided by our previous work in pathogenic fungi, in which very modest HSP90 inhibition impairs resistance to mechanistically diverse antifungals, we examined the effect of similarly modest HSP90 inhibition on the emergence of resistance to antiestrogens in breast cancer models. Even though this degree of inhibition fell below the threshold for proteotoxic activation of the heat-shock response and had no overt anticancer activity on its own, it dramatically impaired the emergence of resistance to hormone antagonists both in cell culture and in mice. Our findings strongly support the clinical testing of combined hormone antagonist-low-level HSP90 inhibitor regimens in the treatment of metastatic estrogen receptor-positive breast cancer. At a broader level, they also provide promising proof of principle for a generalizable strategy to combat the pervasive problem of rapidly emerging resistance to molecularly targeted therapeutics.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; lindquist_admin@wi.mit.edu whitesell@wi.mit.edu.
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115;
authors.forename: Sandro
authors.initials: S
authors.lastname: Santagata
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142;
authors.forename: Marc L
authors.initials: ML
authors.lastname: Mendillo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215;
authors.forename: Nancy U
authors.initials: NU
authors.lastname: Lin
authors.affiliation: Synta Pharmaceuticals, Lexington, MA 02421;
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, MA 02142; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142; and Howard Hughes Medical Institute, Cambridge, MA 02142 lindquist_admin@wi.mit.edu whitesell@wi.mit.edu.
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002453:Cell Cycle; D019008:Drug Resistance, Neoplasm; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology*; D064593:Heterografts; D006801:Humans
chemical_list: D018931:Antineoplastic Agents, Hormonal; D018841:HSP90 Heat-Shock Proteins
keywords: antiestrogen; drug resistance; estrogen receptor; tamoxifen; tumor progression