title: Proliferation of colorectal cancer is promoted by two signaling transduction expression patterns: ErbB2/ErbB3/AKT and MET/ErbB3/MAPK.
abstract: One of the recent breakthroughs in cancer research is the identification of activating mutations in various receptor tyrosine kinase(RTK) pathways in many cancers including colorectal cancer(CRC). We hypothesize that, alternative to mutations, overexpression of various oncogenic RTKs may also underpin CRC pathogenesis, and different RTK may couple with distinct downstream signaling pathways in different subtypes of human CRC. By immunohistochemistry, we show here that RTK members ErbB2, ErbB3 and c-Met were in deed differentially overexpressed in colorectal cancer patient samples leading to constitutive activation of RTK signaling pathways. Using ErbB2 specific inhibitor Lapatinib and c-Met specific inhibitor PHA-665752, we further demonstrated that this constitutive activation of RTK signaling is necessary for the survival of colorectal cancer cells. Furthermore, we show that RTK overexpression pattern dictates the use of downstream AKT and/or MAPK pathways. Our data are important additions to current oncogenic mutation models, and further explain the clinical variation in therapeutic responses of colorectal cancer. Our findings advocate for more personalized therapy tailored to individual patients based on their type of RTK expression in addition to their mutation status.
authors.affiliation: Department of Clinical Laboratory, Kunshan First People's Hospital, Affiliated to Jiangsu University, Kunshan, Jiangsu, China.
authors.forename: Yong-Liang
authors.initials: YL
authors.lastname: Yao
authors.forename: Jie
authors.initials: J
authors.lastname: Shao
authors.forename: Chunfu
authors.initials: C
authors.lastname: Zhang
authors.forename: Jian-Hong
authors.initials: JH
authors.lastname: Wu
authors.forename: Qing-Hui
authors.initials: QH
authors.lastname: Zhang
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009154:Mutation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D013450:Sulfones / Q000494:pharmacology
chemical_list: D007211:Indoles; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D013450:Sulfones; C480541:5-((2,6-dichlorobenzyl)sulfonyl)-3-((3,5-dimethyl-4-((2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl)carbonyl)-1H-pyrrol-2-yl)methylene)-1,3-dihydro-2H-indol-2-one