title: mTOR co-targeting in cetuximab resistance in head and neck cancers harboring PIK3CA and RAS mutations.
abstract: BACKGROUND
  Cetuximab, a monoclonal blocking antibody against the epidermal growth factor receptor EGFR, has been approved for the treatment of squamous cell carcinomas of the head and neck (HNSCC). However, only few patients display long-term responses, prompting the search for cetuximab resistance mechanisms and new therapeutic options enhancing cetuximab effectiveness.
  
  
  METHODS
  Cetuximab-sensitive HNSCC cells were retro-engineered to express PIK3CA and RAS oncogenes. These cells and HNSCC cells harboring endogenous PIK3CA and RAS oncogenes were xenografted into mice (n = 10 per group) and studied for their biochemical, antitumor, antiangiogenic, and antilymphangiogenic responses to cetuximab and mTOR targeting agents. All P values are two-sided.
  
  
  RESULTS
  Cetuximab treatment of PIK3CA- and RAS-expressing HNSCC xenografts promoted an initial antitumor response, but all tumors relapsed within few weeks. In these tumors, cetuximab did not decrease the activity of mTOR, a downstream signaling target of EGFR, PIK3CA, and RAS. The combined administration of cetuximab and mTOR inhibitors exerted a remarkably increased antitumor activity, particularly in HNSCC cells that are resistant to cetuximab as a single agent. Indeed, cotargeting mTOR together with cetuximab caused a rapid tumor collapse of both PIK3CA- and RAS-expressing HNSCC xenografts (P < .001), concomitant with reduced proliferation (P < .001) and lymphangiogenesis (P < .001).
  
  
  CONCLUSIONS
  The presence of PIK3CA and RAS mutations and other alterations affecting the mTOR pathway activity in HNSCC could be exploited to predict the potential resistance to cetuximab, and to select the patients that may benefit the most from the concomitant administration of cetuximab and PI3K and/or mTOR inhibitors as a precision molecular therapeutic option for HNSCC patients.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC).
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC).
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC).
authors.forename: Alfredo A
authors.initials: AA
authors.lastname: Molinolo
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC).
authors.forename: Vyomesh
authors.initials: V
authors.lastname: Patel
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC).
authors.forename: Ramiro
authors.initials: R
authors.lastname: Iglesias-Bartolome
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC).
authors.forename: Maria Sol
authors.initials: MS
authors.lastname: Degese
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC).
authors.forename: Lynn
authors.initials: L
authors.lastname: Vitale-Cross
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC). qmchen@scu.edu.cn sg39v@nih.gov.
authors.forename: Qianming
authors.initials: Q
authors.lastname: Chen
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD (ZW, DM, AAM, VP, RIB, MSD, LVC, JSG); State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China (ZW, QC).
authors.forename: J Silvio
authors.initials: JS
authors.lastname: Gutkind
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D042583:Lymphangiogenesis / Q000187:drug effects; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000903:Antibiotics, Antineoplastic; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C512478:EGFR protein, human
references.citation: Cancer Res. 2011 Nov 15;71(22):7103-12
references.pmid: 21975930
references.citation: Nat Med. 2012 Jan 22;18(2):221-3
references.pmid: 22270724
references.citation: Cancer Prev Res (Phila). 2009 May;2(5):419-22
references.pmid: 19401522
references.citation: Cancer Res. 2007 Sep 1;67(17):8240-7
references.pmid: 17804738
references.citation: Nat Rev Cancer. 2013 Sep;13(9):663-73
references.pmid: 23949426
references.citation: Arch Otolaryngol Head Neck Surg. 1994 Jul;120(7):755-60
references.pmid: 7912510
references.citation: J Natl Cancer Inst. 1998 Jun 3;90(11):824-32
references.pmid: 9625170
references.citation: Head Neck. 2008 May;30(5):667-74
references.pmid: 18383530
references.citation: Mol Oncol. 2013 Jun;7(3):359-68
references.pmid: 23200321
references.citation: Expert Opin Investig Drugs. 2010 Jun;19(6):709-22
references.pmid: 20415598
references.citation: Curr Protoc Hum Genet. 2008 Apr;Chapter 10:Unit 10.11
references.pmid: 18428421
references.citation: Clin Cancer Res. 2006 Jul 1;12(13):4103-11
references.pmid: 16818711
references.citation: Sci Transl Med. 2011 Sep 7;3(99):99ra86
references.pmid: 21900593
references.citation: Oncogene. 2009 Oct 29;28(43):3801-13
references.pmid: 19684613
references.citation: PLoS Med. 2008 Jan 22;5(1):e8
references.pmid: 18215105
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: Cancer Sci. 2006 Dec;97(12):1351-8
references.pmid: 17052259
references.citation: Cancer Res. 1993 Aug 1;53(15):3579-84
references.pmid: 8339264
references.citation: J Clin Oncol. 2006 Jun 10;24(17):2666-72
references.pmid: 16763281
references.citation: J Clin Oncol. 2010 Mar 1;28(7):1254-61
references.pmid: 20100961
references.citation: Clin Cancer Res. 2013 Apr 1;19(7):1858-72
references.pmid: 23444227
references.citation: JAMA Otolaryngol Head Neck Surg. 2013 Jun;139(6):617-22
references.pmid: 23787421
references.citation: Clin Cancer Res. 2007 Sep 1;13(17):4964-73
references.pmid: 17785546
references.citation: Curr Treat Options Oncol. 2012 Mar;13(1):71-81
references.pmid: 22282394
references.citation: Nat Cell Biol. 2011 Feb;13(2):132-41
references.pmid: 21258367
references.citation: Laryngoscope. 2010 Jun;120(6):1159-65
references.pmid: 20513033
references.citation: Oral Oncol. 2011 Oct;47(10):946-50
references.pmid: 21824802
references.citation: Expert Opin Ther Targets. 2011 Jan;15(1):63-74
references.pmid: 21110697
references.citation: Oral Oncol. 2000 Jan;36(1):76-80
references.pmid: 10889924
references.citation: Cancer Prev Res (Phila). 2009 Jan;2(1):27-36
references.pmid: 19139015
references.citation: Nat Rev Clin Oncol. 2009 Sep;6(9):519-27
references.pmid: 19636327
references.citation: Blood. 2008 Jan 1;111(1):379-82
references.pmid: 17878402
references.citation: Genes Dev. 2004 Aug 15;18(16):1926-45
references.pmid: 15314020
references.citation: Clin Cancer Res. 2014 May 1;20(9):2300-11
references.pmid: 24599934
references.citation: Lancet Oncol. 2010 Jan;11(1):21-8
references.pmid: 19897418
references.citation: J Clin Oncol. 2006 Sep 1;24(25):4170-6
references.pmid: 16943533
references.citation: N Engl J Med. 2008 Sep 11;359(11):1116-27
references.pmid: 18784101
references.citation: Cancer Discov. 2013 Jul;3(7):761-9
references.pmid: 23619167
references.citation: Cancer Prev Res (Phila). 2012 Apr;5(4):562-73
references.pmid: 22467081
references.citation: Oncogene. 1997 Jul 24;15(4):409-16
references.pmid: 9242377
references.citation: Clin Cancer Res. 2012 May 1;18(9):2558-68
references.pmid: 22409888
references.citation: Clin Cancer Res. 2006 Mar 1;12(5):1441-6
references.pmid: 16533766
references.citation: Cancer Discov. 2013 Jul;3(7):722-5
references.pmid: 23847349
references.citation: Nat Rev Cancer. 2007 Mar;7(3):169-81
references.pmid: 17318210
references.citation: Cancer Res. 2005 Nov 1;65(21):9953-61
references.pmid: 16267020
references.citation: Mol Oncol. 2014 Feb;8(1):105-18
references.pmid: 24216180
references.citation: Cancer Res. 2008 Feb 15;68(4):1144-53
references.pmid: 18281490
references.citation: BMC Cancer. 2013 Jul 01;13:320
references.pmid: 23815869
references.citation: Oncogene. 2008 Jun 26;27(28):3944-56
references.pmid: 18297114
references.citation: Nat Rev Clin Oncol. 2010 Sep;7(9):493-507
references.pmid: 20551942
references.citation: Cancer Sci. 2006 Oct;97(10):1115-24
references.pmid: 16984384
references.citation: Cancer Res. 2010 Jul 15;70(14):5942-52
references.pmid: 20634405
references.citation: Cancer Discov. 2013 Jul;3(7):770-81
references.pmid: 23619168
references.citation: Clin Cancer Res. 2009 Mar 1;15(5):1585-92
references.pmid: 19190133
references.citation: Cancer Res. 2009 May 15;69(10):4159-66
references.pmid: 19435901
references.citation: Int J Otolaryngol. 2013;2013:848021
references.pmid: 23737793
references.citation: Cytokine Growth Factor Rev. 2002 Feb;13(1):41-59
references.pmid: 11750879
references.citation: N Engl J Med. 2006 Feb 9;354(6):567-78
references.pmid: 16467544