title: PI3K/mTOR inhibitor PF-04691502 antitumor activity is enhanced with induction of wild-type TP53 in human xenograft and murine knockout models of head and neck cancer.
abstract: OBJECTIVE
  Phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway activation is often associated with altered expression or mutations of PIK3CA, TP53/p73, PTEN, and TGF-β receptors (TGFBR) in head and neck squamous cell carcinomas (HNSCC). However, little is known about how these alterations affect response to PI3K/mTOR-targeted agents.
  
  
  METHODS
  In this preclinical study, PI3K/Akt/mTOR signaling was characterized in nine HNSCC (UM-SCC) cell lines and human oral keratinocytes. We investigated the molecular and anticancer effects of dual PI3K/mTOR inhibitor PF-04691502(PF-502) in UM-SCC expressing PIK3CA with decreased wild-type TP53, mutant TP53-/+ mutantTGFBR2, and in HNSCC of a conditional Pten/Tgfbr1 double knockout mouse model displaying PI3K/Akt/mTOR activation.
  
  
  RESULTS
  UM-SCC showed increased PIK3CA expression and Akt/mTOR activation, and PF-502 inhibited PI3K/mTORC1/2 targets. In human HNSCC expressing PIK3CA and decreased wtTP53 and p73, PF-502 reciprocally enhanced TP53/p73 expression and growth inhibition, which was partially reversible by p53 inhibitor pifithrin-α. Most UM-SCC with wtTP53 exhibited a lower IC50 than those with mtTP53 status. PF-502 blocked growth in G0-G1 and increased apoptotic sub-G0 DNA. PF-502 suppressed tumorigenesis and showed combinatorial activity with radiation in a wild-type TP53 UM-SCC xenograft model. PF-502 also significantly delayed HNSCC tumorigenesis and prolonged survival of Pten/Tgfbr1-deficient mice. Significant inhibition of p-Akt, p-4EBP1, p-S6, and Ki67, as well as increased p53 and TUNEL were observed in tumor specimens.
  
  
  CONCLUSIONS
  PI3K-mTOR inhibition can enhance TP53/p73 expression and significantly inhibit tumor growth alone or when combined with radiation in HNSCC with wild-type TP53. PIK3CA, TP53/p73, PTEN, and TGF-β alterations are potential modifiers of response and merit investigation in future clinical trials with PI3K-mTOR inhibitors.
authors: Tumor Biology Section, Head and Neck Surgery Branch, National Institute on Deafness and Other Communication Disorders, NIH, Bethesda, Maryland 20892, USA.
authors: Amanda
authors: A
authors: Herzog
authors: Yansong
authors: Y
authors: Bian
authors: Robert
authors: R
authors: Vander Broek
authors: Bradford
authors: B
authors: Hall
authors: Jamie
authors: J
authors: Coupar
authors: Hui
authors: H
authors: Cheng
authors: Anastasia L
authors: AL
authors: Sowers
authors: John D
authors: JD
authors: Cook
authors: James B
authors: JB
authors: Mitchell
authors: Zhong
authors: Z
authors: Chen
authors: Ashok B
authors: AB
authors: Kulkarni
authors: Carter
authors: C
authors: Van Waes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D052160:Benzothiazoles / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D015533:Transcriptional Activation; D047368:Tumor Burden / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D052160:Benzothiazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D014050:Toluene; D016159:Tumor Suppressor Protein p53; C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; C495901:TP53 protein, human; C121565:pifithrin; C546842:MTOR protein, human
references: Mol Cancer Ther. 2011 Nov;10(11):2189-99
references: 21750219
references: Cancer Res. 2001 Aug 1;61(15):5911-8
references: 11479233
references: Cancer Res. 2009 Jul 15;69(14):5918-26
references: 19584284
references: Science. 2011 Aug 26;333(6046):1157-60
references: 21798893
references: Clin Cancer Res. 2007 Sep 1;13(17):4964-73
references: 17785546
references: Head Neck. 2010 Dec;32(12):1619-28
references: 20222045
references: N Engl J Med. 2007 Dec 20;357(25):2552-61
references: 18094376
references: Oncogene. 2010 Nov 18;29(46):6160-71
references: 20729916
references: J Clin Oncol. 1999 Sep;17(9):2909-14
references: 10561370
references: J Pathol. 2002 Nov;198(3):335-42
references: 12375266
references: Int J Cancer. 2002 Jun 1;99(4):538-48
references: 11992543
references: Science. 1999 Sep 10;285(5434):1733-7
references: 10481009
references: Cancer Res. 2009 Apr 15;69(8):3415-24
references: 19351843
references: Cancer Sci. 2006 Dec;97(12):1351-8
references: 17052259
references: Oncotarget. 2010 Nov;1(7):530-43
references: 21317449
references: Eur J Cancer B Oral Oncol. 1994 Sep;30B(5):338-45
references: 7703804
references: Expert Opin Ther Targets. 2011 Jan;15(1):63-74
references: 21110697
references: Clin Cancer Res. 2012 Oct 1;18(19):5304-13
references: 22859719
references: Cancer Res. 2011 Dec 15;71(24):7351-9
references: 21987725
references: Cancer Prev Res (Phila). 2009 Jan;2(1):27-36
references: 19139015
references: Clin Cancer Res. 2012 Dec 15;18(24):6771-83
references: 23136191
references: Cancer Res. 2011 Nov 1;71(21):6867-77
references: 21933882
references: Cancer Res. 2008 Sep 1;68(17):7066-72
references: 18757421
references: Br J Cancer. 2012 Jan 3;106(1):107-15
references: 22116303
references: PLoS One. 2012;7(3):e33396
references: 22413021
references: Clin Cancer Res. 2012 May 1;18(9):2558-68
references: 22409888
references: Clin Cancer Res. 2007 Nov 15;13(22 Pt 1):6568-78
references: 18006756
references: Genes Dev. 2006 May 15;20(10):1331-42
references: 16702406
references: Oral Oncol. 2009 Apr-May;45(4-5):324-34
references: 18805044
references: Cancer Res. 2005 Nov 1;65(21):9953-61
references: 16267020
references: Clin Cancer Res. 2004 Sep 1;10(17):5820-7
references: 15355912
references: Laryngoscope. 2011 Nov;121(11):2359-65
references: 22020886
references: Curr Opin Genet Dev. 2010 Feb;20(1):87-90
references: 20006486
references: Cell Stem Cell. 2012 Sep 7;11(3):401-14
references: 22958932
references: Head Neck. 2010 Apr;32(4):417-26
references: 19760794
references: Cancer Res. 2009 May 15;69(10):4159-66
references: 19435901
references: Cancer Res. 2007 Mar 1;67(5):2160-8
references: 17332346
references: Proc Natl Acad Sci U S A. 2011 Feb 1;108(5):2076-81
references: 21245298
references: Oncogene. 2009 Feb 26;28(8):1151-61
references: 19137016
references: Oncogene. 2012 Jul 12;31(28):3322-32
references: 22037217
references: Clin Cancer Res. 2008 Dec 15;14(24):8094-101
references: 19073969
references: PLoS One. 2012;7(2):e31331
references: 22355357