Colorectal cancer (CRC) is a major cause of morbidity and mortality. It accounts for over 9% of all malignancies, making it the third most common cancer worldwide and second most common cause of death in the developed world. Treatment of metastatic colorectal cancer (mCRC) is largely palliative, making potentially curative therapy via molecular inhibition of specific cellular targets in CRC a highly sought-after goal. However, the complexity and non-intuitive nature of cancer signaling pathways have made the development of effective targeted drugs a major challenge. One target that has been the focus of considerable 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 (panitumumab or cetuximab)[1]. In the trial that led to FDA approval of cetuximab in mCRC, response rate to single agent cetuximab in patients who had progressed on prior chemotherapy was only 11%[2]. Subsequently it was shown that tumors with activating mutations in KRAS (KRASMUT) do not benefit from EGFR blockade [3]. Given the ubiquitous expression of EGFR in CRC, why does such a large subset of patients fail to benefit from anti-EGFR antibodies? The most straightforward explanation for failure of anti-EGFR therapy in KRASMUT CRC is that the constitutive activity of KRASMUT bypasses activation of the EGF receptor lying upstream. But this does not explain the primary resistance in patients whose tumors have wild-type KRAS. The finding of heterogeneous effects of anti-EGFR treatment in wild-type tumors as well as in those with different subsets of KRAS mutations [4] emphasizes the need to improve our understanding of the mechanisms, which underlie both responsiveness and primary resistance to these therapies. The oncogenic mutation in KRAS traps this small GTPase in the active GTP-bound state, leading to strong pro-proliferation and anti-differentiation signals. Illustrative of the potency of RAS, 30% of all metastatic cancers carry somatic KRAS mutations, such as KRASG12D, and approximately 40% in CRC [1, 4]. Of note, the quest for small molecules that revert the trapped active KRAS