A subset of colorectal carcinomas express c-KIT protein independently of BRAF and/or KRAS activation.
c-KIT is a tyrosine kinase receptor found to be overexpressed in several tumours, namely, GISTs, breast, lung, prostate, ovarian and colorectal carcinomas (CRC). We aimed at determining the frequency of c-KIT expression and mutations in a series of 109 CRC cases (73 primary tumours and 36 lymph node metastases) characterised for KRAS and BRAF mutations. We also aimed at analysing the cellular effects of STI571/Gleevec in CRC-derived cell lines displaying c-KIT expression and KRAS or BRAF mutations. By immunohistochemistry, we found c-KIT overexpression in 15% (11/73) of primary tumours and in 14% (5/36) of metastasis; however, cases showing overexpression did not show c-kit mutations in hotspot regions. The majority (64%) of primary tumours with c-KIT overexpression had mutations at KRAS-BRAF genes. The same was true for 60% of the metastases. We treated CRC cell lines with STI571/Gleevec and verified that it inhibits proliferation and induces apoptosis in all cell lines. In conclusion, overexpression of c-KIT is observed in a subset of primary and CRC metastases in the absence of c-kit mutations. STI571/Gleevec increases apoptosis in CRC cell lines independently of its genetic profile, suggesting that STI571/Gleevec is likely to be an alternative drug for the clinical trials of CRC.
Preto
Ana
A
Institute of Molecular Pathology and Immunology of the University of Porto, Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal. apreto@ipatimup.pt
Moutinho
Cátia
C
Velho
Sérgia
S
Oliveira
Carla
C
Rebocho
Ana Paula
AP
Figueiredo
Joana
J
Soares
Paula
P
Lopes
José Manuel
JM
Seruca
Raquel
R
D000970:Antineoplastic Agents / Q000494:pharmacology; D001483:Base Sequence; D001549:Benzamides; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000145:classification* / Q000378:metabolism* / Q000473:pathology; D004252:DNA Mutational Analysis; D015870:Gene Expression; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis / Q000235:genetics; D008969:Molecular Sequence Data; D009154:Mutation; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras); D011743:Pyrimidines / Q000494:pharmacology; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; C117307:KRAS protein, human; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins