title: Activated cMET and IGF1R-driven PI3K signaling predicts poor survival in colorectal cancers independent of KRAS mutational status.
abstract: BACKGROUND
  Oncogenic mutational analysis provides predictive guidance for therapeutics such as anti-EGFR antibodies, but it is successful only for a subset of colorectal cancer (CRC) patients.
  
  
  METHODS
  A comprehensive molecular profiling of 120 CRC patients, including 116 primary, 15 liver metastasis, and 1 peritoneal seeding tissue samples was performed to identify the relationship between v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) WT and mutant CRC tumors and clinical outcomes. This included determination of the protein activation patterns of human epidermal receptor 1 (HER1), HER2, HER3, c-MET, insulin-like growth factor 1 receptor (IGF1R), phosphatidylinositide 3-kinase (PI3K), Src homology 2 domain containing (Shc), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK) kinases using multiplexed collaborative enzyme enhanced reactive (CEER) immunoassay.
  
  
  RESULTS
  KRAS WT and mutated CRCs were not different with respect to the expression of the various signaling molecules. Poor prognosis in terms of early relapse (<2 years) and shorter disease-free survival (DFS) correlated with enhanced activation of PI3K signaling relative to the HER kinase pathway signaling, but not with the KRAS mutational status. KRAS WT CRCs were identified as a mixed prognosis population depending on their level of PI3K signaling. KRAS WT CRCs with high HER1/c-MET index ratio demonstrated a better DFS post-surgery. c-MET and IGF1R activities relative to HER axis activity were considerably higher in early relapse CRCs, suggesting a role for these alternative receptor tyrosine kinases (RTKs) in driving high PI3K signaling.
  
  
  CONCLUSIONS
  The presented data subclassified CRCs based on their activated signaling pathways and identify a role for c-MET and IGF1R-driven PI3K signaling in CRCs, which is superior to KRAS mutational tests alone. The results from this study can be utilized to identify aggressive CRCs, explain failure of currently approved therapeutics in specific CRC subsets, and, most importantly, generate hypotheses for pathway-guided therapeutic strategies that can be tested clinically.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jeeyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: Research and Development, Oncology, Prometheus Laboratories, San Diego, California, United States of America.
authors.forename: Anjali
authors.initials: A
authors.lastname: Jain
authors.affiliation: Research and Development, Oncology, Prometheus Laboratories, San Diego, California, United States of America.
authors.forename: Phillip
authors.initials: P
authors.lastname: Kim
authors.affiliation: Research and Development, Oncology, Prometheus Laboratories, San Diego, California, United States of America.
authors.forename: Tani
authors.initials: T
authors.lastname: Lee
authors.affiliation: Research and Development, Oncology, Prometheus Laboratories, San Diego, California, United States of America.
authors.forename: Anne
authors.initials: A
authors.lastname: Kuller
authors.affiliation: Research and Development, Oncology, Prometheus Laboratories, San Diego, California, United States of America.
authors.forename: Fred
authors.initials: F
authors.lastname: Princen
authors.affiliation: Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.lastname: In-GuDo
authors.affiliation: Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Suk Hyeong
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Joon Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Young Suk
authors.initials: YS
authors.lastname: Park
authors.affiliation: Research and Development, Oncology, Prometheus Laboratories, San Diego, California, United States of America.
authors.forename: Sharat
authors.initials: S
authors.lastname: Singh
authors.affiliation: Departments of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hee Cheol
authors.initials: HC
authors.lastname: Kim
mesh_terms: D000368:Aged; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met; D017526:Receptor, IGF Type 1; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
references.citation: Clin Colorectal Cancer. 2005 Apr;5 Suppl 1:S28-33
references.pmid: 15871763
references.citation: Clin Cancer Res. 2013 May 15;19(10):2688-98
references.pmid: 23549875
references.citation: Br J Cancer. 2013 Apr 30;108(8):1757-64
references.pmid: 23511557
references.citation: Mol Cancer Res. 2009 Jun;7(6):955-65
references.pmid: 19509113
references.citation: Br J Cancer. 2011 Mar 15;104(6):1020-6
references.pmid: 21364579
references.citation: PLoS One. 2011;6(9):e25132
references.pmid: 21966435
references.citation: N Engl J Med. 2009 Apr 2;360(14):1408-17
references.pmid: 19339720
references.citation: N Engl J Med. 1988 Sep 1;319(9):525-32
references.pmid: 2841597
references.citation: JAMA. 2010 Oct 27;304(16):1812-20
references.pmid: 20978259
references.citation: Proteome Sci. 2011 Dec 15;9(1):75
references.pmid: 22172159
references.citation: Oncogene. 2013 May 9;32(19):2463-74
references.pmid: 22751112
references.citation: J Clin Oncol. 2012 Aug 20;30(24):2956-62
references.pmid: 22665543
references.citation: J Clin Invest. 2011 Nov;121(11):4311-21
references.pmid: 21985784
references.citation: J Clin Oncol. 2012 Mar 10;30(8):765-6
references.pmid: 22271482
references.citation: J Clin Oncol. 2010 Mar 1;28(7):1254-61
references.pmid: 20100961
references.citation: Lancet Oncol. 2010 Aug;11(8):753-62
references.pmid: 20619739
references.citation: N Engl J Med. 2008 Oct 23;359(17):1757-65
references.pmid: 18946061
references.citation: Proc Natl Acad Sci U S A. 1999 Apr 13;96(8):4240-5
references.pmid: 10200246
references.citation: PLoS One. 2009;4(2):e4584
references.pmid: 19240792
references.citation: Cell. 2007 Jun 1;129(5):957-68
references.pmid: 17540175
references.citation: Curr Opin Pharmacol. 2008 Aug;8(4):413-8
references.pmid: 18619559
references.citation: Pathol Res Pract. 2007;203(7):489-97
references.pmid: 17629419
references.citation: J Clin Oncol. 2009 Apr 20;27(12):2091-6
references.pmid: 19188670
references.citation: J Clin Oncol. 2007 Nov 20;25(33):5225-32
references.pmid: 18024868
references.citation: J Clin Oncol. 2010 Nov 1;28(31):4697-705
references.pmid: 20921465
references.citation: Sci Transl Med. 2013 Jul 31;5(196):196ra99
references.pmid: 23903756