title: Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST).
abstract: BACKGROUND
  c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance.
  
  
  METHODS
  RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting.
  
  
  RESULTS
  Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 µM to IM respectively. GIST48 have an IC50 0.66 µM to IM, 0.91 µM to amuvatinib [AMU] and 0.67 µM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63).
  
  
  CONCLUSIONS
  Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.
authors.affiliation: West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN.
authors.forename: Daruka
authors.initials: D
authors.lastname: Mahadevan
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Noah
authors.initials: N
authors.lastname: Theiss
authors.affiliation: West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN.
authors.forename: Carla
authors.initials: C
authors.lastname: Morales
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Stejskal
authors.affiliation: West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN.
authors.forename: Laurence S
authors.initials: LS
authors.lastname: Cooke
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Min
authors.initials: M
authors.lastname: Zhu
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Drew
authors.initials: D
authors.lastname: Kurtzman
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Rachel
authors.initials: R
authors.lastname: Swart
authors.affiliation: University of Arizona Cancer Center, Tucson, AZ.
authors.forename: Evan
authors.initials: E
authors.lastname: Ong
authors.affiliation: West Cancer Center/University of Tennessee Health Science Center (UTHSC), Memphis, TN.
authors.forename: Wenqing
authors.initials: W
authors.lastname: Qi
mesh_terms: D000077716:Afatinib; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods; D010879:Piperazines; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013890:Thiourea; D000094963:Axl Receptor Tyrosine Kinase
chemical_list: D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D011799:Quinazolines; D000077716:Afatinib; D000068877:Imatinib Mesylate; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D019009:Proto-Oncogene Proteins c-kit; D019859:Proto-Oncogene Proteins c-met; D020794:Receptor Protein-Tyrosine Kinases; D013890:Thiourea; C521047:amuvatinib; D000094963:Axl Receptor Tyrosine Kinase; C000722289:AXL protein, human