PMID- 22491422
OWN - NLM
STAT- MEDLINE
DCOM- 20120625
LR  - 20211021
IS  - 1532-1827 (Electronic)
IS  - 0007-0920 (Print)
IS  - 0007-0920 (Linking)
VI  - 106
IP  - 8
DP  - 2012 Apr 10
TI  - Cross-suppression of EGFR ligands amphiregulin and epiregulin and de-repression 
      of FGFR3 signalling contribute to cetuximab resistance in wild-type KRAS tumour 
      cells.
PG  - 1406-14
LID - 10.1038/bjc.2012.103 [doi]
AB  - BACKGROUND: In addition to the mutational status of KRAS, the epidermal growth 
      factor receptor (EGFR) ligands amphiregulin (AREG) and epiregulin (EREG) might 
      function as bona fide biomarkers of cetuximab (Ctx) sensitivity for most 
      EGFR-driven carcinomas. METHODS: Lentivirus-delivered small hairpin RNAs were 
      employed to specifically reduce AREG or EREG gene expression in wild-type KRAS 
      A431 squamous cell carcinoma cells. Colony-forming assays were used to monitor 
      the impact of AREG and EREG knockdown on Ctx efficacy. Amphiregulin and EREG 
      protein expression levels were assessed by quantitative ELISA in parental A431 
      cells and in pooled populations of A431 cells adapted to grow in the presence of 
      Ctx. A phosphoproteomic platform was used to measure the relative level of 
      phosphorylation of 42 distinct receptor tyrosine kinases before and after the 
      acquisition of resistance to Ctx. RESULTS: Stable gene silencing of either ligand 
      was found to notably reduce the expression of the other ligand. Parental A431 
      cells with normal expression levels of AREG/EREG exhibited significantly 
      increased growth inhibition in response to Ctx, compared with derivatives that 
      are engineered to produce minimal AREG/EREG. The parental A431 cells acutely 
      treated with Ctx exhibited reduced basal expression levels of AREG/EREG. Pooled 
      populations of Ctx-resistant A431 cells expressed significantly lower levels of 
      AREG/EREG and were insensitive to the downregulatory effects of Ctx. 
      Phosphoproteomic screen identified a remarkable hyperactivation of FGFR3 in 
      Ctx-resistant A431 cells, which gained sensitivity to the cytotoxic and apoptotic 
      effects of the FGFR3 TK inhibitor PD173074. The A431 parental cells acutely 
      treated with Ctx rapidly activated FGFR3 and their concomitant exposure to Ctx 
      and PD173074 resulted in synergistic apoptosis. CONCLUSION: Cross-suppression of 
      AREG/EREG expression may explain the tight co-expression of AREG and EREG, as 
      well as their tendency to be more highly expressed than other EGFR ligands to 
      determine Ctx efficacy. The positive selection for Ctx-resistant tumour cells 
      exhibiting AREG/EREG cross-suppression may have an important role in the 
      emergence of Ctx resistance. As de-repression of FGFR3 activity rapidly replaces 
      the loss of EGFR-ligand signalling in terms of cell proliferation and survival, 
      combinations of Ctx and FGFR3-targeted drugs may be a valuable strategy to 
      enhance the efficacy of single Ctx while preventing or delaying acquired 
      resistance to Ctx.
FAU - Oliveras-Ferraros, C
AU  - Oliveras-Ferraros C
AD  - Unit of Translational Research, Catalan Institute of Oncology, Girona, Spain.
FAU - Cufi, S
AU  - Cufi S
FAU - Queralt, B
AU  - Queralt B
FAU - Vazquez-Martin, A
AU  - Vazquez-Martin A
FAU - Martin-Castillo, B
AU  - Martin-Castillo B
FAU - de Llorens, R
AU  - de Llorens R
FAU - Bosch-Barrera, J
AU  - Bosch-Barrera J
FAU - Brunet, J
AU  - Brunet J
FAU - Menendez, J A
AU  - Menendez JA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Cancer
JT  - British journal of cancer
JID - 0370635
RN  - 0 (AREG protein, human)
RN  - 0 (Amphiregulin)
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (EGF Family of Proteins)
RN  - 0 (EREG protein, human)
RN  - 0 (Epiregulin)
RN  - 0 (Glycoproteins)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Ligands)
RN  - 0 (PD 173074)
RN  - 0 (Pyrimidines)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 3)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
MH  - Amphiregulin
MH  - Antibodies, Monoclonal/*pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/pharmacology
MH  - Apoptosis/drug effects
MH  - Cell Survival/drug effects
MH  - Cetuximab
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - EGF Family of Proteins
MH  - Epidermal Growth Factor/*antagonists & inhibitors/biosynthesis/genetics
MH  - Epiregulin
MH  - ErbB Receptors/*metabolism
MH  - Gene Knockdown Techniques
MH  - Glycoproteins/*antagonists & inhibitors/biosynthesis/genetics
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/biosynthesis/genetics
MH  - Ligands
MH  - Pyrimidines/pharmacology
MH  - Receptor, Fibroblast Growth Factor, Type 3/*metabolism
MH  - Signal Transduction/*drug effects
MH  - Skin Neoplasms/drug therapy/*pathology
MH  - Structure-Activity Relationship
MH  - Tumor Cells, Cultured
PMC - PMC3326676
COIS- Cristina Oliveras-Ferraros received a research salary from a Grant Award by the 
      'Fundacion Salud 2000', which is promoted by Merck Serono (Madrid, Spain). All 
      other authors declare no conflict of interest.
EDAT- 2012/04/12 06:00
MHDA- 2012/06/26 06:00
PMCR- 2013/04/10
CRDT- 2012/04/12 06:00
PHST- 2012/04/12 06:00 [entrez]
PHST- 2012/04/12 06:00 [pubmed]
PHST- 2012/06/26 06:00 [medline]
PHST- 2013/04/10 00:00 [pmc-release]
AID - bjc2012103 [pii]
AID - 10.1038/bjc.2012.103 [doi]
PST - ppublish
SO  - Br J Cancer. 2012 Apr 10;106(8):1406-14. doi: 10.1038/bjc.2012.103.