Abstract Nutrient restriction, also known as caloric restriction, has been extensively examined for its positive impact on lifespan, immune system boost, and aging. Nutrient restriction, defined as providing essential nutrients but restricting total caloric intake, has shown to decrease disease rate in humans. In addition, nutrient restriction is implicated in decreasing cancer initiation and progression. We have previously established three dimensional cell culture models, known as spheroids, in the HCT 116 colorectal cancer cell line as a high throughput model for studying the proteomic changes associated with nutrient restriction. We found that SUMOylated proteins are up regulated in colorectal cancer 3D cell cultures when subjected to metabolic stress. The attachment of the SUMO protein leads to changes in subcellular location, DNA repair, transcriptional regulation, and mitosis. We will explore SUMOylated in response to nutrient restriction via a novel technique to detect biomolecules using LC-SERS. This method allows the can detection of chemical differences associated with biomolecule structure. We first will enhance this system to detect and quantify metabolites in a more complex matrix, such as a cell lysate. Once the methodology has been optimized we use LC-SERS to identify and quantitate SUMOylated proteins in response to NR. When compared to available MS methods to identified SUMOylated proteins, we hypothesize our novel LC-SERS methodology will be able to surpass the limitations found with MS methods. Nutrient restriction has overwhelming effects on cancer and this study will provides further evidence that SUMOlyation, in response to metabolic stress, has a role in cancer progression. Citation Format: Monica M. Schroll, Zachary D. Schultz, Amanda B. Hummon. Combination of liquid chromatography-surface enhanced Raman spectroscopy and liquid chromatography-mass spectrometry to identify SUMOylated proteins due to nutrient restriction in colorectal cancer. [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 B42.