The use of protein array to identify targetable receptor tyrosine kinases for treatment of human colon cancer.
Several studies have reported that activated receptor tyrosine kinases (RTKs) are highly expressed in colon cancer and may promote tumor growth and survival. However, there is little information available as to the function and signaling of RTKs in colon cancers. In the present study, we performed protein array technology to determine the expression status of various RTKs that are activated in colon cancer compared to normal colonic cells and tissues. Of the 42 different phospho-RTKs, 5 (ErbB2, FGFR1, FGFR2a, FGFR3 and MSPR) were activated in Caco-2, SW480, WiDr, Lovo colon cancer cell lines and cancerous tissues. In order to determine the effect of inhibition of RTKs, especially ErbB2, athymic nude mice bearing xenograft tumors were treated with the ErbB2-targeting drug trastuzumab alone, or in combination with 5-Fluorouracil (5-FU). Similar to the treatment of 5-FU alone, trastuzumab suppressed the growth of colon cancer. Combination therapy of trastuzumab and 5-FU inhibited tumor growth significantly compared to the treatment of 5-FU alone or trastuzumab alone. In addition, xenograft tumors were also analyzed by phospho-MAPK protein array. The activity of Akt3/PKBgamma was inhibited with 5-FU alone and trastuzumab, indicating that trastuzumab may inhibit colon cancer growth through ErbB2-Akt3/PKBgamma signaling. These data demonstrate that ErbB2 could be an important candidate for colon cancer therapy and the addition of trastuzumab to 5-FU therapy might augment the clinical response in colon cancer patients. Therefore, the analysis of phospho-RTK expression by protein array as a useful tool might identify novel therapies for individual patients with colon cancer.
Morishita
Asahiro
A
Department of Medicine, Columbia University, College of Physicians & Surgeons, NY 10032, USA. am2925@columbia.edu
Gong
Jian
J
Nomura
Takako
T
Yoshida
Hirohito
H
Izuishi
Kunihiko
K
Suzuki
Yasuyuki
Y
Kushida
Yoshio
Y
Haba
Reiji
R
D'Armiento
Jeanine
J
Masaki
Tsutomu
T
D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D018938:Caco-2 Cells; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D058990:Molecular Targeted Therapy; D010766:Phosphorylation; D040081:Protein Array Analysis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D000068878:Trastuzumab; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005472:Fluorouracil; D020928:Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C491754:AKT3 protein, human