PMID- 21833472
OWN - NLM
STAT- MEDLINE
DCOM- 20120120
LR  - 20181201
IS  - 1791-2423 (Electronic)
IS  - 1019-6439 (Linking)
VI  - 39
IP  - 6
DP  - 2011 Dec
TI  - Interferon/STAT1 and neuregulin signaling pathways are exploratory biomarkers of 
      cetuximab (Erbitux(R)) efficacy in KRAS wild-type squamous carcinomas: a 
      pathway-based analysis of whole human-genome microarray data from 
      cetuximab-adapted tumor cell-line models.
PG  - 1455-79
LID - 10.3892/ijo.2011.1155 [doi]
AB  - KRAS mutation status is being used as the sole biomarker to predict therapeutic 
      efficacy of cetuximab in metastatic colorectal cancer (mCRC). A significant 
      number of mCRC patients with KRAS wild-type (WT) tumors, however, do not benefit 
      from cetuximab. We are also lacking efficacy predictors in head and neck squamous 
      cell carcinomas with an intact KRAS signaling and in non-small cell lung cancer 
      in which KRAS mutations do not predict cetuximab efficacy. We recently 
      established pre-clinical models of EGFR gene-amplified KRAS WT A431 squamous 
      carcinoma cells chronically adapted to grow in the presence of cetuximab. We 
      employed the ingenuity pathway analysis software to functionally interpret data 
      from Agilent's whole human genome arrays in the context of biological processes, 
      networks, and pathways. Cetuximab-induced activation of the interferon 
      (IFN)/STAT1 appeared to switch from 'growth inhibitory' in acutely-treated cells 
      to 'pro-survival' in chronically-adapted cells. Cetuximab treatment appeared to 
      negatively select initially dominant IFN-sensitive clones and promoted selection 
      of IFN- and cetuximab-refractory tumor clones constitutively bearing an 
      up-regulated IFN/STAT1 signaling. High-levels of mRNAs coding for the EGFR 
      ligands amphiregulin (AREG), epiregulin (EREG), and neuregulin-1/heregulin (NRG1) 
      predicted for acute cetuximab's functioning. Chronic cetuximab, however, appeared 
      to negatively select initially dominant AREG/EREG/NRG1-positive clones to promote 
      selection of cetuximab-refractory clones exhibiting a knocked-down neuregulin 
      signaling. Our current evolutionary mapping of the transcriptomic changes that 
      occur during cetuximab-induced chronic blockade of EGFR/KRAS WT signaling 
      strongly suggests that mRNAs coding for IFN/STAT1- and EGFR ligands-related genes 
      can be evaluated as novel predictors of efficacy in KRAS WT squamous cancer 
      patients being treated with cetuximab.
FAU - Oliveras-Ferraros, Cristina
AU  - Oliveras-Ferraros C
AD  - Unit of Translational Research, Catalan Institute of Oncology-Girona, 
      (ICO-Girona), E-17007 Girona, Catalonia, Spain.
FAU - Vazquez-Martin, Alejandro
AU  - Vazquez-Martin A
FAU - Queralt, Bernardo
AU  - Queralt B
FAU - Adrados, Manuel
AU  - Adrados M
FAU - Ortiz, Rosa
AU  - Ortiz R
FAU - Cufi, Silvia
AU  - Cufi S
FAU - Hernandez-Yague, Xavier
AU  - Hernandez-Yague X
FAU - Guardeno, Raquel
AU  - Guardeno R
FAU - Baez, Luciana
AU  - Baez L
FAU - Martin-Castillo, Begona
AU  - Martin-Castillo B
FAU - Perez-Martinez, Maria Carmen
AU  - Perez-Martinez MC
FAU - Lopez-Bonet, Eugeni
AU  - Lopez-Bonet E
FAU - De Llorens, Rafael
AU  - De Llorens R
FAU - Bernado, Luis
AU  - Bernado L
FAU - Brunet, Joan
AU  - Brunet J
FAU - Menendez, Javier A
AU  - Menendez JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110809
PL  - Greece
TA  - Int J Oncol
JT  - International journal of oncology
JID - 9306042
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Biomarkers)
RN  - 0 (KRAS protein, human)
RN  - 0 (Neuregulins)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (STAT1 Transcription Factor)
RN  - 0 (STAT1 protein, human)
RN  - 9008-11-1 (Interferons)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras))
RN  - EC 3.6.5.2 (ras Proteins)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
MH  - Antibodies, Monoclonal/pharmacology/*therapeutic use
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/pharmacology/*therapeutic use
MH  - Biomarkers/metabolism
MH  - Carcinoma, Squamous Cell/*drug therapy/genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cetuximab
MH  - ErbB Receptors/antagonists & inhibitors
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic
MH  - Gene Regulatory Networks
MH  - Genome, Human
MH  - Genome-Wide Association Study
MH  - Humans
MH  - Interferons/*pharmacology
MH  - Models, Biological
MH  - Neuregulins/*metabolism
MH  - Oligonucleotide Array Sequence Analysis
MH  - Proto-Oncogene Proteins/*genetics
MH  - Proto-Oncogene Proteins p21(ras)
MH  - STAT1 Transcription Factor/*metabolism
MH  - Signal Transduction/drug effects
MH  - ras Proteins/*genetics
EDAT- 2011/08/13 06:00
MHDA- 2012/01/21 06:00
CRDT- 2011/08/12 06:00
PHST- 2011/04/27 00:00 [received]
PHST- 2011/06/17 00:00 [accepted]
PHST- 2011/08/12 06:00 [entrez]
PHST- 2011/08/13 06:00 [pubmed]
PHST- 2012/01/21 06:00 [medline]
AID - 10.3892/ijo.2011.1155 [doi]
PST - ppublish
SO  - Int J Oncol. 2011 Dec;39(6):1455-79. doi: 10.3892/ijo.2011.1155. Epub 2011 Aug 9.