Colorectal cancer (CRC) is a common and deadly condition. Worldwide, there are approximately 1.8 million new cases per year and 881,000 death per year, making it the third most prevalent and second most lethal cancer. In the Unites states alone, there were approximately 150,000 new cases and 53,000 deaths in 2020.2 It is estimated that by 2035 there may be 2.5 million new cases of CRC per year worldwide.3 While improved screening and treatments have lengthened survival, the 5-year survival probability of metastatic CRC (mCRC) is only about 12%. While immunotherapy is often effective in mCRC patients with microsatellite instability (MSI-H), patients with microsatellite stable (MSS) disease do not respond. In patients with microsatellite stable (MSS) mCRC, first- and second-line treatments are typically cytotoxic chemotherapy (combinations of oxaliplatin, irinotecan, fluorouracil, and capecitabine) with or without inhibitors of the epidermal growth factor receptor (EGFR, poor response if RAS/BRAF mutant or right-sided) and vascular endothelial growth factor (VEGF, bevacizumab). Novel treatment strategies for MSS mCRC are desperately needed, both in the maintenance and refractory settings. We hypothesize that selinexor in combination with DNA damaging chemotherapy (5- FU, capecitabine, and/or irinotecan) will synergize to generate DNA damage, cell cycle arrest, and apoptosis, producing promising anti-tumor efficacy in CRC patient-derived xenograft (PDX) models. Bevacizumab, when added to selinexor with or without chemotherapy, may also synergistically block VEGF signaling pathways, resulting in promising anti-tumor efficacy. We will characterize the efficacy, toxicity, mechanisms of action, and importance of KRAS mutational status to inform clinical trial development. In Aim 1, we will evaluate the response of selinexor as a single agent and in combination with DNA damaging agents and evaluate the anti- proliferative effects in patient-derived organoids (PDOs). Additionally, we use existing WES and whole transcriptome analysis to assess the molecular characteristics of the PDOs that determine response. In Aim 2, we will use the corresponding PDX models that responded in Aim 1 and assess the ability to predict response. Additionally, we will use IHC, and immunoblotting to determine the mechanism of response to these agents.