title: Development of a RSK Inhibitor as a Novel Therapy for Triple-Negative Breast Cancer.
abstract: Metastatic breast cancer is an incurable disease and identification of novel therapeutic opportunities is vital. Triple-negative breast cancer (TNBC) frequently metastasizes and high levels of activated p90RSK (RSK), a downstream MEK-ERK1/2 effector, are found in TNBC. We demonstrate, using direct pharmacologic and genetic inhibition of RSK1/2, that these kinases contribute to the TNBC metastatic process in vivo Kinase profiling showed that RSK1 and RSK2 are the predominant kinases targeted by the new inhibitor, which is based on the natural product SL0101. Further evidence for selectivity was provided by the observations that silencing RSK1 and RSK2 eliminated the ability of the analogue to further inhibit survival or proliferation of a TNBC cell line. In vivo, the new derivative was as effective as the FDA-approved MEK inhibitor trametinib in reducing the establishment of metastatic foci. Importantly, inhibition of RSK1/2 did not result in activation of AKT, which is known to limit the efficacy of MEK inhibitors in the clinic. Our results demonstrate that RSK is a major contributor to the TNBC metastatic program and provide preclinical proof-of-concept for the efficacy of the novel SL0101 analogue in vivo Mol Cancer Ther; 15(11); 2598-608. ©2016 AACR.
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Ludwik
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: J Preston
authors.initials: JP
authors.lastname: Campbell
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University, Boston, Massachusetts.
authors.forename: Mingzong
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University, Boston, Massachusetts.
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Zachary M
authors.initials: ZM
authors.lastname: Sandusky
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Lejla
authors.initials: L
authors.lastname: Pasic
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Miranda E
authors.initials: ME
authors.lastname: Sowder
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: David R
authors.initials: DR
authors.lastname: Brenin
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.|Department of Biochemistry, Vanderbilt University, Nashville, Tennessee.|Department of Otolaryngology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Pietenpol
authors.affiliation: Department of Chemistry & Chemical Biology, Northeastern University, Boston, Massachusetts.
authors.forename: George A
authors.initials: GA
authors.lastname: O'Doherty
authors.affiliation: Department of Pathology, Microbiology & Immunology, Vanderbilt University, Nashville, Tennessee. deborah.lannigan@vanderbilt.edu.|Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lannigan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D009005:Monosaccharides / Q000737:chemistry / Q000494:pharmacology; D009362:Neoplasm Metastasis; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001578:Benzopyrans; D009005:Monosaccharides; D047428:Protein Kinase Inhibitors; C497449:SL0101; D051057:Proto-Oncogene Proteins c-akt; D038744:Ribosomal Protein S6 Kinases, 90-kDa