Kinase Suppressor of Ras 1 (KSR1), a molecular scaffold for the Raf/MEK/ERK kinase cascade, is required for transformation and survival of cells bearing oncogenic Ras, but is not required for normal cell survival. KSR1 knockout mice are phenotypically normal, and depletion of KSR1 by RNAi does not kill immortalized, non-transformed human colon epithelial cells (HCECs), suggesting that KSR1 or KSR1-dependent effectors may serve as highly selective therapeutic targets. Our previous work showed that KSR1 regulates expression of the transcription factor peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1β), whose expression is critical to colon cancer cell survival. Using RNAi and pharmacological inhibition, we observed that KSR1 and ERK drive both cap-dependent and cap-independent translation of Myc in human colon tumor cell lines, which increases PGC1β mRNA expression (McCall et al. MCB, 2016). This effect is mediated through the KSR1 and ERK-dependent phosphorylation of 4E-PB1 and phosphorylation-dependent loss of PDCD4 that reverses their inhibitory effect on eIF4E and eIF4A, respectively. Treatment with ERK inhibitor SCH772984 showed that ERK regulates PDCD4 protein expression and 4EBP1 phosphorylation to promote Myc expression in four of the seven colon cancer cell lines. These observations suggest that KSR1-dependent regulation of translation may be a common mechanism used to support tumor cell survival. Using KSR1 as a reference standard, Functional Signature Ontology (FUSION, Potts et al. Sci. Signaling 2013) was used to identify genetic vulnerabilities in human colon tumor cells that are absent in HCECs. Comparison of results from this screen to genome-wide polysome profiling data from cells transformed with Ras and Myc (Truitt et al. Cell 2015) identified 25 candidate mRNAs with altered translational efficiency that are predicted to support the survival of human colon tumor cells. These data suggest that KSR1 and ERK-dependent alteration of the translational landscape is a common strategy used to support colon tumor cell survival. Identification of mRNAs preferentially translated in colon tumor cells may yield novel targets for therapeutic manipulation and may provide unique markers with which to classify colon tumors, predict patient outcome, and select effective treatment. This abstract is also being presented as Poster B36. Citation Format: Eyerusalem M. Lemma, Jamie L. McCall, Beth K. Clymer, David L. Kelly, Michael A. White, Robert E. Lewis. Translational control of human colon tumor cell survival. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr PR04.