title: RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer.
abstract: The PI3K signaling pathway regulates diverse cellular processes, including proliferation, survival, and metabolism, and is aberrantly activated in human cancer. As such, numerous compounds targeting the PI3K pathway are currently being clinically evaluated for the treatment of cancer, and several have shown some early indications of efficacy in breast cancer. However, resistance against these agents, both de novo and acquired, may ultimately limit the efficacy of these compounds. Here, we have taken a systematic functional approach to uncovering potential mechanisms of resistance to PI3K inhibitors and have identified several genes whose expression promotes survival under conditions of PI3K/mammalian target of rapamycin (PI3K/mTOR) blockade, including the ribosomal S6 kinases RPS6KA2 (RSK3) and RPS6KA6 (RSK4). We demonstrate that overexpression of RSK3 or RSK4 supports proliferation upon PI3K inhibition both in vitro and in vivo, in part through the attenuation of the apoptotic response and upregulation of protein translation. Notably, the addition of MEK- or RSK-specific inhibitors can overcome these resistance phenotypes, both in breast cancer cell lines and patient-derived xenograft models with elevated levels of RSK activity. These observations provide a strong rationale for the combined use of RSK and PI3K pathway inhibitors to elicit favorable responses in breast cancer patients with activated RSK.
authors: Experimental Therapeutics, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
authors: Violeta
authors: V
authors: Serra
authors: Pieter J A
authors: PJ
authors: Eichhorn
authors: Celina
authors: C
authors: García-García
authors: Yasir H
authors: YH
authors: Ibrahim
authors: Ludmila
authors: L
authors: Prudkin
authors: Gertrudis
authors: G
authors: Sánchez
authors: Olga
authors: O
authors: Rodríguez
authors: Pilar
authors: P
authors: Antón
authors: Josep-Lluís
authors: JL
authors: Parra
authors: Sara
authors: S
authors: Marlow
authors: Maurizio
authors: M
authors: Scaltriti
authors: José
authors: J
authors: Pérez-Garcia
authors: Aleix
authors: A
authors: Prat
authors: Joaquín
authors: J
authors: Arribas
authors: William C
authors: WC
authors: Hahn
authors: So Young
authors: SY
authors: Kim
authors: José
authors: J
authors: Baselga
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology; D016366:Open Reading Frames; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; D007093:Imidazoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C548887:MK 2206; C571178:NVP-BKM120; C501305:RPS6KA6 protein, human; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; C531198:dactolisib
references: Nat Rev Drug Discov. 2009 Aug;8(8):627-44
references: 19644473
references: PLoS One. 2012;7(5):e38033
references: 22675430
references: Nat Chem Biol. 2011 Sep 25;7(11):787-93
references: 21946274
references: Oncogene. 2007 Feb 1;26(5):683-700
references: 16878154
references: Biochem J. 2007 Dec 15;408(3):297-315
references: 17850214
references: J Clin Oncol. 2012 Jan 20;30(3):282-90
references: 22162589
references: Curr Opin Genet Dev. 2010 Feb;20(1):87-90
references: 20006486
references: Clin Cancer Res. 2009 Jul 15;15(14):4649-64
references: 19567590
references: Clin Proteomics. 2010 Dec;6(4):129-51
references: 21691416
references: J Biol Chem. 2007 May 11;282(19):14056-64
references: 17360704
references: Lancet. 2008 Aug 9;372(9637):449-56
references: 18653228
references: Int J Cancer. 2012 Jul 15;131(2):E45-55
references: 22020623
references: Nat Med. 2011 Aug 07;17(9):1116-20
references: 21822287
references: N Engl J Med. 2012 Feb 9;366(6):520-9
references: 22149876
references: Mol Cancer Ther. 2008 Jul;7(7):1851-63
references: 18606717
references: Nature. 2012 Mar 28;483(7391):603-7
references: 22460905
references: Nature. 2004 Mar 25;428(6981):431-7
references: 15042092
references: Nat Rev Cancer. 2009 Aug;9(8):550-62
references: 19629070
references: J Exp Med. 2011 Aug 29;208(9):1799-807
references: 21859846
references: Mol Cancer Ther. 2012 Feb;11(2):317-28
references: 22188813
references: Mol Cell Biol. 2010 Jun;30(11):2621-35
references: 20351173
references: Mol Cell. 2010 Oct 22;40(2):310-22
references: 20965424
references: Science. 1996 Aug 16;273(5277):959-63
references: 8688081
references: Biochemistry. 1989 May 30;28(11):4729-34
references: 2548591
references: Mol Cell Biol. 1990 Mar;10(3):1134-44
references: 2304461
references: Cancer Res. 2004 May 1;64(9):3014-21
references: 15126336
references: Nat Biotechnol. 2010 Dec;28(12):1248-50
references: 21139605
references: Anticancer Agents Med Chem. 2008 Oct;8(7):710-6
references: 18855572
references: Clin Cancer Res. 2012 Apr 15;18(8):2316-25
references: 22261800
references: N Engl J Med. 2011 Feb 10;364(6):514-23
references: 21306238
references: Clin Cancer Res. 2010 Jul 15;16(14):3670-83
references: 20453058
references: PLoS Biol. 2009 Feb 10;7(2):e38
references: 19209957
references: Curr Opin Cell Biol. 2009 Apr;21(2):194-8
references: 19201591
references: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22299-304
references: 20007781
references: Cancer Res. 2005 Feb 1;65(3):1027-34
references: 15705904
references: Clin Cancer Res. 2009 Jul 15;15(14):4546-53
references: 19584160
references: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):E699-708
references: 21876152
references: J Clin Oncol. 2012 Mar 10;30(8):777-82
references: 22271473
references: J Clin Invest. 2010 Aug;120(8):2858-66
references: 20664172
references: Proc Natl Acad Sci U S A. 2010 Jan 26;107(4):1565-70
references: 20080688
references: Mol Cancer Ther. 2011 Mar;10(3):558-65
references: 21216929
references: Clin Cancer Res. 2008 Jul 15;14(14):4427-36
references: 18628456
references: Carcinogenesis. 2011 Apr;32(4):470-6
references: 21239520
references: Cancer Res. 2005 Apr 15;65(8):3108-16
references: 15833840
references: Genes Dev. 2010 Dec 1;24(23):2654-65
references: 21062900
references: Genes Chromosomes Cancer. 2004 Oct;41(2):117-24
references: 15287024
references: EMBO J. 2006 Jun 21;25(12):2781-91
references: 16763566
references: Oncogene. 2011 Jun 2;30(22):2547-57
references: 21278786
references: Clin Cancer Res. 2007 Mar 1;13(5):1576-83
references: 17332304
references: Nat Methods. 2011 Jun 26;8(8):659-61
references: 21706014
references: Mol Cancer Res. 2007 Feb;5(2):171-81
references: 17314274
references: Biochem J. 2012 Jan 15;441(2):553-69
references: 22187936
references: Nat Rev Genet. 2011 Jun 17;12(7):487-98
references: 21681210
references: Anal Biochem. 1994 May 1;218(2):314-9
references: 8074286
references: Nature. 2010 Dec 16;468(7326):968-72
references: 21107320
references: Cancer Res. 2008 Oct 1;68(19):8022-30
references: 18829560
references: Nat Med. 2008 Dec;14(12):1351-6
references: 19029981
references: Nat Rev Cancer. 2010 Apr;10(4):254-66
references: 20332778
references: Nat Med. 2012 Jun;18(6):892-901
references: 22610277
references: J Biol Chem. 2005 Apr 8;280(14):13304-14
references: 15632195
references: Mol Cell Biol. 1996 Oct;16(10):5328-34
references: 8816444
references: Cancer Res. 2008 Nov 15;68(22):9221-30
references: 19010894
references: Cancer Discov. 2012 Nov;2(11):1036-47
references: 22915752
references: Mol Cancer Ther. 2012 Sep;11(9):2062-71
references: 22723336
references: Nat Rev Mol Cell Biol. 2008 Oct;9(10):747-58
references: 18813292
references: Oncogene. 2011 Jul 21;30(29):3222-33
references: 21358673
references: Cancer Cell. 2011 Jan 18;19(1):58-71
references: 21215704