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Structural variants (SVs) within the cancer genome reflect defects in DNA damage repair, impact gene regulation, and alter the genomic landscape. SVs impact a larger fraction of the cancer genome than any other genetic aberration, yet their effects on modulating therapeutic response have been largely uncharacterized. Patterns of rearrangements, otherwise known as signatures, vary across tumor and tissue type, and can indicate underlying biological mechanisms responsible for cancer etiology. We have extracted SV signatures from whole genome sequencing data from hundreds of cancer cell lines. Using datasets indicating the cell lines’ response to over a thousand small molecule inhibitors, we have identified associations between SV signatures and response to therapeutics. These results will enhance our understanding of mechanisms underlying rearrangement signatures and nominate new biomarkers of drug response. Citation Format: Simona Dalin, Frank Dubois, Shu Zhang, Alexander Crane, Jeremie Kalfon, Javad Noorbakhsh, Rameen Beroukhim. Associations between structural variant signatures and drug sensitivity in cell lines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2710.