Suppressive signals in colorectal cancer: RasGRP1 a new marker for anti-EGFR therapy?

Abstract

625 Background: Treatment of metastatic colorectal cancer (mCRC) is largely palliative, making potentially curative therapy via molecular inhibition of specific cellular targets in CRC is a highly sought-after goal. One target of considerable focus in both basic and clinical investigation in CRC is the Epidermal Growth Factor Receptor (EGFR). Despite widespread EGFR expression in CRC, clinical trials have shown modest benefit from the use of anti-EGFR blocking antibodies and tumors with activating mutations in KRAS (KRASMUT) do not benefit from EGFR blockade. Given the ubiquitous expression of EGFR in CRC, why does such a large subset of patients fail to benefit from anti-EGFR antibodies? Methods: We combine the analysis of genetic mouse models, CRC cell line, and CRC patient database information and tumor samples. Results: We recently reported that two structurally distinct types of RasGEFs, SOS1 and RasGRP1, are co-expressed in both normal intestinal epithelial cells and in CRC cells. We observed that EGFR signals in CRC cells with KRASMUT result in even more RAS activation, arguing that RasGEFs load more RAS molecules with GTP following EGF stimulation. Indeed, we found that both SOS1 and RasGRP1 are activated downstream of the EGFR. Quite surprisingly, SOS1 and RasGRP1 have opposing functions here. Biochemically, RasGRP1 limits the amount of EGFR-SOS1-RAS signals. Biologically, knockdown of RasGRP1 expression in KRASMUT CRC cells leads to increased tumor growth in a xenograft mouse model. Conclusions: We hypothesize that anti-EGFR therapy may lead to unwanted inhibition of the inhibitory EGFR signals when CRC tumor express significant levels of RasGRP1 protein. We will discuss our current research that focuses on RasGRP1 as a prognostic marker of CRC outcome but also as a diagnostic indicator for EGFR therapy.