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Is sorafenib effective in colorectal cancer? Definition of resistance indicators and impact of potential comedications.

e14126 Background: We initiated this study in order to analyse the value of sorafenib in colorectal cancer and to define potential combination chemotherapeutics and resistance indicators.


METHODS
The expression of diverse targeted tyrosine kinases was analysed in 103 colorectal cancer samples and correlated with clinico-pathologic parameters. The effect of increasing sorafenib doses on proliferation, apoptosis, migration, invasion and activation of signal cascades was analysed in vitro. In addition, the efficacy of a sorafenib monotherapy and different combination therapies was analysed in vitro (sorafenib +/- 5-FU, irinotecan or oxalipaltin) and in vivo (sorafenib +/- 5-FU).


RESULTS
The expression of VEGFR3 and PDGFRα correlated with lymphatic metastatic disease (P=0.06 and P=0.01, respectively) and with distant metastases (VEGFR3; P=0.06). In vitro, SW480 and HT29 cell lines were sorafenib sensitive, whereas Caco2 and SW620 cell lines were resistant, independent of the mutation status of K-ras, Raf, PTEN or PI3K. The effect on migration and invasion was marginal, but distinct differences in caspases activation were seen. Combination strategies were beneficial in some settings (sorafenib+5-FU; irinotecan) and disadvantageous in others (sorafenib+oxaliplatin), depending on the chemotherapeutic drug and cell line chosen. In vivo, the combination of sorafenib + 5-FU was not superior to the respective monotherapy. Sensitive cell lines revealed a down-regulation of AKT and had a hint expression-level of GADD45ß. In resistant cell lines, pp53 and GADD45ß levels decreased upon sorafenib exposure.


CONCLUSIONS
Sensitivity to sorafenib and combination-therapies exists in certain settings and definition of resistance indicators such as GADD45ß might help to select patients for future studies.