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Ovarian cancer is the most common cause of gynecological cancer death in women in United States. Up to 70% of all ovarian cancer cases are high-grade serous carcinomas with 5-year survival rates less than 30%. Recent studies have suggested the importance of the cholesterol pathway in multiple cancers including gynecological malignancies. Here we demonstrate that genetic or pharmacological disturbance of cholesterol pathway in high-grade serous ovarian carcinoma cell lines results in significant changes in survival rate after drug treatment, and in protein and RNA expression patterns. SREBP2 is a transcription factor encoded by SREBF2 gene that regulates expression of sterol-regulated genes and thus maintains cholesterol homeostasis. To assess the role of SREBP2 in ovarian cancer we have created a stable OVCAR8 cell line with SREBF2 disrupted using CRISPR technology. This SREBF2-KD line has reduced SREBF2 mRNA and protein expression level that indicates an effective gene knockdown. Activation of SREBF2 is dependent on the cholesterol status of the cell. We observed that expression of the SREBP2 precursor form is significantly reduced in SREBF2-KD line when cells are maintained under low serum conditions. Mutant cells treated with paclitaxel in low, but not high serum or in presence of statin, revealed significantly lower cell viability. SREBF2-KD cells do not survive long-term, high concentrations of paclitaxel, nor do they grow back as efficiently as control cells. RNA expression and proteomic analysis revealed the critical regulators mediating SREBP2 activity in stressed cells. Together, these observations suggest that the cholesterol pathway is critical for ovarian cancer cells not only to resist stresses, such as chemotherapy, but also to return to a high proliferation state upon recurrence. Further studies will provide important targets for developing new drugs for treatment of ovarian cancer. Citation Format: Galina Karashchuk, Nataliya Karashchuk, Signe Caksa, Tyler S. Smith, Alexander S. Brodsky. Cholesterol pathway determines ovarian cancer drug resistance through transcription factor SREBP2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4409. doi:10.1158/1538-7445.AM2017-4409