title: TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF-mutant melanoma.
abstract: RAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) inhibitors are effective in treating patients with BRAF-mutant melanoma. However, most responses are partial and short-lived, and many patients fail to respond at all. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein S6 (P-S6), effectively predicted induction of cell death by the inhibitor in BRAF-mutant melanoma cell lines. In resistant melanomas, TORC1 activity was maintained after treatment with RAF or MEK inhibitors, in some cases despite robust suppression of mitogen-activated protein kinase (MAPK) signaling. In in vivo mouse models, suppression of TORC1 after MAPK inhibition was necessary for induction of apoptosis and tumor response. Finally, in paired biopsies obtained from patients with BRAF-mutant melanoma before treatment and after initiation of RAF inhibitor therapy, P-S6 suppression predicted significantly improved progression-free survival. Such a change in P-S6 could be readily monitored in real time by serial fine-needle aspiration biopsies, making quantitation of P-S6 a valuable biomarker to guide treatment in BRAF-mutant melanoma.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
authors.forename: Ryan B
authors.initials: RB
authors.lastname: Corcoran
authors.forename: Stephen Michael
authors.initials: SM
authors.lastname: Rothenberg
authors.forename: Aaron N
authors.initials: AN
authors.lastname: Hata
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.forename: Adriano
authors.initials: A
authors.lastname: Piris
authors.forename: Rosalynn M
authors.initials: RM
authors.lastname: Nazarian
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Brown
authors.forename: Jason T
authors.initials: JT
authors.lastname: Godfrey
authors.forename: Daniel
authors.initials: D
authors.lastname: Winokur
authors.forename: John
authors.initials: J
authors.lastname: Walsh
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wargo
authors.forename: Keith T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D000076222:Mechanistic Target of Rapamycin Complex 1; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D038601:Ribosomal Protein S6 / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D038601:Ribosomal Protein S6; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
references.citation: Nat Rev Drug Discov. 2009 Aug;8(8):627-44
references.pmid: 19644473
references.citation: N Engl J Med. 2010 Aug 26;363(9):809-19
references.pmid: 20818844
references.citation: N Engl J Med. 2012 Jul 12;367(2):107-14
references.pmid: 22663011
references.citation: Nat Rev Cancer. 2009 Aug;9(8):550-62
references.pmid: 19629070
references.citation: Cancer Cell. 2004 Jul;6(1):91-9
references.pmid: 15261145
references.citation: Nat Rev Clin Oncol. 2010 Apr;7(4):209-19
references.pmid: 20234352
references.citation: Nature. 2010 Dec 16;468(7326):968-72
references.pmid: 21107320
references.citation: Oncotarget. 2011 Apr;2(4):336-46
references.pmid: 21505228
references.citation: Cancer Discov. 2011 Sep;1(4):352-65
references.pmid: 22145099
references.citation: Nat Rev Cancer. 2012 Apr 05;12(5):349-61
references.pmid: 22475929
references.citation: Nature. 2012 Jul 26;487(7408):505-9
references.pmid: 22763448
references.citation: Sci Transl Med. 2013 Jul 31;5(196):196ra99
references.pmid: 23903756
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 17;106(46):19503-8
references.pmid: 19850869
references.citation: Oncogene. 2012 Jan 26;31(4):446-57
references.pmid: 21725359
references.citation: N Engl J Med. 2012 Feb 23;366(8):707-14
references.pmid: 22356324
references.citation: Nature. 2012 Jul 26;487(7408):500-4
references.pmid: 22763439
references.citation: J Biol Chem. 2003 May 23;278(21):18811-6
references.pmid: 12646560
references.citation: Ann Oncol. 2009 Aug;20 Suppl 6:vi22-9
references.pmid: 19617294
references.citation: J Clin Oncol. 2010 Feb 20;28(6):1075-83
references.pmid: 20085938
references.citation: Nature. 2010 Dec 16;468(7326):973-7
references.pmid: 21107323
references.citation: J Med Chem. 2008 Sep 25;51(18):5522-32
references.pmid: 18754654
references.citation: Biochem J. 2012 Jan 1;441(1):1-21
references.pmid: 22168436
references.citation: Nature. 2011 Nov 23;480(7377):387-90
references.pmid: 22113612
references.citation: Clin Cancer Res. 2007 Aug 15;13(16):4934-42
references.pmid: 17652623
references.citation: N Engl J Med. 2011 Jun 30;364(26):2507-16
references.pmid: 21639808
references.citation: Cancer Res. 2010 Jan 1;70(1):288-98
references.pmid: 20028854
references.citation: Cancer Res. 2010 Nov 1;70(21):8736-47
references.pmid: 20959481
references.citation: Cell. 2006 Mar 24;124(6):1283-98
references.pmid: 16564017
references.citation: Cancer Res. 2008 May 1;68(9):3421-8
references.pmid: 18451170
references.citation: Lancet Oncol. 2010 Apr;11(4):391-400
references.pmid: 20106719
references.citation: Nature. 2002 Jun 27;417(6892):949-54
references.pmid: 12068308
references.citation: Sci Signal. 2010 Nov 23;3(149):ra84
references.pmid: 21098728
references.citation: Nature. 2010 Sep 30;467(7315):596-9
references.pmid: 20823850
references.citation: Nat Med. 2008 Dec;14(12):1351-6
references.pmid: 19029981
references.citation: J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94
references.pmid: 19812304
references.citation: Genes Dev. 2003 Aug 1;17(15):1829-34
references.pmid: 12869586
references.citation: J Biol Chem. 2007 May 11;282(19):14056-64
references.pmid: 17360704
references.citation: Lancet Oncol. 2012 Aug;13(8):782-9
references.pmid: 22805292
references.citation: Cancer Cell. 2010 Dec 14;18(6):683-95
references.pmid: 21156289
references.citation: Nat Commun. 2012 Mar 06;3:724
references.pmid: 22395615
references.citation: Proc Natl Acad Sci U S A. 2004 Sep 14;101(37):13489-94
references.pmid: 15342917
references.citation: N Engl J Med. 2012 Nov;367(18):1694-703
references.pmid: 23020132
references.citation: Mol Cancer Ther. 2008 Jul;7(7):1851-63
references.pmid: 18606717
references.citation: Lancet. 2012 Jul 28;380(9839):358-65
references.pmid: 22735384
references.citation: Cell. 2005 Apr 22;121(2):179-93
references.pmid: 15851026
references.citation: Cancer J. 2011 Nov-Dec;17(6):505-11
references.pmid: 22157295