title: KRAS allel-specific activity of sunitinib in an isogenic disease model of colorectal cancer.
abstract: OBJECTIVE
  To investigate the impact of different KRAS mutations on treatment with the tyrosine kinase inhibitor sunitinib in SW48 colorectal cancer cell line variants.
  
  
  METHODS
  Isogenic SW48 KRAS wt, G12A, G12C, G12D, G12R, G12S, G12 V, and G13D cells were evaluated for ERK phosphorylation with and without EGF stimulation. In addition, the respective cell lines were tested for the effect of sunitinib on ERK/ELK phosphorylation, cell cycle, and cytotoxicity.
  
  
  RESULTS
  Compared to KRAS wt cells, all KRAS mutant variants were associated with resistance to sunitinib treatment. In the MTT chemosensitivity assay, the grade of resistance was less pronounced in G13D and highest in G12A, G12C, and G12S mutant cells. The reduction in ERK phosphorylation due to treatment with sunitinib was highest in G12V (89 %) mutant cells and lowest in G12A (24 %) mutant cells. ELK phosphorylation was less decreased in all KRAS mutant variants compared to KRAS wt cells following sunitinib treatment. The grade of resistance appears to correlate with the individual KRAS-dependent intrinsic activation of ERK.
  
  
  CONCLUSIONS
  Our isogenic cell culture model suggests that KRAS mutations in SW48 colorectal cancer cells are linked to resistance to the multityrosine kinase inhibitor sunitinib. KRAS G13D mutant SW48 cells represented the KRAS subspecies with the lowest grade of resistance. Future studies will have to clarify whether KRAS can be used to guide sunitinib treatment or-in general-a treatment with a multityrosine kinase inhibitor in mCRC.
authors: Department of Medicine III, University Hospital Grosshadern, University of Munich, Munich, Germany. dominik.modest@med.uni-muenchen.de
authors: D P
authors: DP
authors: Modest
authors: P
authors: P
authors: Camaj
authors: V
authors: V
authors: Heinemann
authors: B
authors: B
authors: Schwarz
authors: A
authors: A
authors: Jung
authors: R P
authors: RP
authors: Laubender
authors: S
authors: S
authors: Gamba
authors: C
authors: C
authors: Haertl
authors: S
authors: S
authors: Stintzing
authors: S
authors: S
authors: Primo
authors: C J
authors: CJ
authors: Bruns
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011758:Pyrroles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077210:Sunitinib; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494112:ELK1 protein, human; D007211:Indoles; D011758:Pyrroles; D050807:ets-Domain Protein Elk-1; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras); D000077210:Sunitinib