Presence of KRAS and BRAF oncogenic mutations sensitise colorectal tumours to TRAIL induced apoptosis: evidence from cell and animal models translated to the clinic

Konference: 2009 34st Congress ESMO a 15th Congress ECCO - účast ČR

Kategorie: Kolorektální karcinom

Téma: Poster Session V: Gastro-intestinal malignancies - colorectal cancer

Číslo abstraktu: P-6126

Autoři: A. Pintzas; E. Oikonomou; RNDr. Ladislav Anděra, CSc.; G. Zografos; G. Kontogeorgos; V. Kosmidou

Background: Most data on the therapeutic potential and expression of TRAIL in colorectal cancer has come from in vitro studies using tumour cell lines. To gain a clearer understanding about the susceptibility of patient tumours to TRAIL, we derived primary human cancer epithelial cells [1]. Increased apoptosis was observed in both primary PAP60 and MIH55 after treatment with SuperKiller TRAIL. Treating patient tumour xenograft/SCID mouse models with Killer TRAIL in vivo for 5 consecutive days suppressed tumour growth, although less efficiently compared to in vitro experiments. Sensitization to TRAIL induced apoptosis by RAS has been previously shown by our lab [2] and by others. We have presented evidence that this effect is usually mediated by TRAIL receptor DR4 and DR5 overexpression and/or redistribution in cell models [3].

Materials and Methods: Primary colorectal tumour cells, colorectal cell lines, mouse xenographs and colorectal clinical samples were either treated with recombinant TRAIL and/or analysed for the presence of oncogenic mutations and DR4, DR5 expression.

Results: We present evidence that DR5 as the most frequently upregulated DR in clinical samples of colon cancer. Furthermore, the presence of K-RAS and BRAF mutations in the tumour may directly or indirectly enhance DR expression, potentially sensitising these otherwise resistant tumours to TRAIL-based therapies [4].

Discussion: Mutations on K-RAS and BRAF oncogenes have been shown in many studies to be associated with resistance to several targeted therapeutics and combinations. TRAIL-based therapeutics, other as mono- or combination therapy could provide a promising alternative for K-RAS/BRAF bearing colorectal tumours.


  1. Oikonomou, E., Kothonidis, K., Taoufik, E., Probert, L., Zografos, G., Nasioulas, G., Andera, L., and Pintzas, A. (2007). Br. J. Cancer. 97, 73–84.
  2. Drosopoulos, K. Roberts, M., Cermak, L., Sasazuki, T., Shirasawa, S., Andera L. and Pintzas, A. (2005). J. Biol. Chem. 280, 22856–22867.
  3. Psahoulia, F. H., Drosopoulos K. G., Doubravska, L., Andera, L. and Pintzas, A. (2007). Mol. Cancer. Ther 6, 2591–2599.
  4. Oikonomou, E., Kosmidou, V., Katseli, A., Kothonidis, K., Mourtzoukou, D., Kontogeorgos, G., Andera, L., Zografos, G., and Pintzas, A. (2009). Under revision.

Publikováno v: European Journal of Cancer Supplements, Vol 7 No 2, September 2009, Page 360

Datum přednesení příspěvku: 23. 9. 2009