title: EGFR- and VEGF(R)-targeted small molecules show synergistic activity in colorectal cancer models refractory to combinations of monoclonal antibodies.
abstract: OBJECTIVE
  Epidermal growth factor receptor (EGFR) and VEGF(R) signaling show extensive cross-talk, providing a rationale for joint targeting of the two pathways. However, combinations of monoclonal antibodies (mAb) targeting EGFR and VEGF showed disappointing activity in patients with colorectal cancer (CRC). We speculated that inhibition of surface receptors and ligands might only partly prevent oncogenic signaling whereas small-molecule tyrosine kinase inhibitors (TKI) would also influence intracellular signaling.
  
  
  METHODS
  Mice with CRC xenografts were treated with two TKIs, vargatef and afatinib, or with two mAbs, bevacizumab and cetuximab, and their influence on tumor growth, viability, in vivo DNA synthesis, and the presence of phosphorylated EGFR and VEGFR was determined. The activity of the TKIs was further characterized in CRC cells with different KRAS status.
  
  
  RESULTS
  Vargatef and afatinib together showed strong tumor growth inhibition toward HT-29 xenografts compared with either drug alone, which was associated with a 5-fold increase in apoptotic tumor cell death. In comparison, bevacizumab and cetuximab together were exclusively cytostatic with no more activity than either drug alone. Exposure to the two TKIs was accompanied by a marked decrease of tumor-associated intracellular phospho-VEGFR1 and phospho-EGFR, whereas similar exposure to the two mAbs had no detectable effect. A synergistic activity of vargatef plus afatinib was observed in all eight CRC cell lines examined, independent of KRAS status.
  
  
  CONCLUSIONS
  Our results indicate that attenuation of intracellular EGFR and/or VEGF signaling is required for cytotoxic activity. These findings provide a rationale for trials of the TKIs, even in patients with mutant KRAS.
authors: Laboratory of Cancer Biology and Therapeutics, Centre de Recherche Saint-Antoine, Paris, France.
authors: Virginie
authors: V
authors: Poindessous
authors: Djamila
authors: D
authors: Ouaret
authors: Karima
authors: K
authors: El Ouadrani
authors: Aude
authors: A
authors: Battistella
authors: Virginie F
authors: VF
authors: Mégalophonos
authors: Nyam
authors: N
authors: Kamsu-Kom
authors: Amélie
authors: A
authors: Petitprez
authors: Alexandre E
authors: AE
authors: Escargueil
authors: Pascaline
authors: P
authors: Boudou
authors: Sylvie
authors: S
authors: Dumont
authors: Pascale
authors: P
authors: Cervera
authors: Jean-François
authors: JF
authors: Fléjou
authors: Thierry
authors: T
authors: André
authors: Christophe
authors: C
authors: Tournigand
authors: Benoist
authors: B
authors: Chibaudel
authors: Aimery
authors: A
authors: de Gramont
authors: Annette K
authors: AK
authors: Larsen
mesh_terms: D000077716:Afatinib; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D019073:HT29 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000494:pharmacology; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007211:Indoles; D011799:Quinazolines; D000068258:Bevacizumab; D000077716:Afatinib; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; C530716:nintedanib; D000068818:Cetuximab