BenCPP2011

Colorectal cancer is a major public health issue as the 2nd cause of cancer-related mortality in Western countries. In approximately half of the cases, patients qualify for curative surgery, whilst the other half, presenting locally advanced tumor, primary or secondary metastasis, require chemotherapy. Unfortunately, tumors frequently develop resistances due to the multiple molecular changes they undergo. For this reason, the median survival time for metastatic patients is only 24 months. Despite recent progress in pharmacology, anti-cancer medicine is still too often administrated without taking into consideration individual molecular and genetic differences. As consequence, anti-cancer treatment is still frequently unsuccessful, both due to the phenomena of tumor resistance to drugs and to their toxic effect on normal tissue. Despite the successive application of several therapeutics, tumor escape causes metastasis. Thus, an essential objective for improved efficiency is the determination of the basis of tumor resistance prior treatment. Such treatment may then be optimized and customized to suit each individual patient. The goal of this 4-year project is to optimize colorectal cancer treatment through the early prediction of response and resistance of tumor escape. We formulate the hypothesis that successive events reaching a tumor development include the inhibition of cell cycle checkpoints and the blocking of death cell mechanisms. Consequently, the cellular transformation induced by oncogenes is associated with intrinsic resistance processes to anti-tumor drugs. So, we propose the oncogenic signaling pathway EGFR/ras induces resistances to genotoxic treatments by inactivating the checkpoints of the cell cycle. Our hypothesis is that the pathway EGFR/ras transforms the “tumor suppressor NF-kB2” into the “oncogenic NF-kB2”. We suggest that the reprogramming of NF-kB2 by the oncogenic EGFR/ras pathway inhibits the autophagy required to the correct establishment of the senescence. This autophagy default decreases the efficiency of the protective mechanisms and promotes the escape from the senescence. This bypass is usually associated with a resistance to anti-tumoral treatments. Furthermore, we speculate that the transcription factor STAT3 might potentialize the oncogenic functions of NF-kB2 following Ras induction. This project will improve the central role of NF-kB2-regulated autophagy in the protective mechanisms against oncogenes. The characterization of the different NF-kB2 complexes associated to their functions might be an important predictive marker in colon cancer. To conclude, the tumors presenting an activation of the oncogenic signaling pathway of EGFR/ras/NF-kB2-STAT3 would be associated with a bad survival prognosis. The presence an intrinsic-resistance program could help the cell to escape from conventional anti-cancer treatments, and would make the early detection of these tumors important for the adaptation and the use of targeted therapies.