Abstract 3974: Investigating doxorubicin resistance in fibrosarcoma

Abstract

Abstract Cytotoxic chemotherapy has been the backbone of medical oncology for nearly a century for multiple cancer types. However, when treating advanced or metastatic disease toxicity, side effects, and acquired resistance often limit the duration of therapy. While randomized control trials have traditionally served as the proving ground for first and subsequent line therapies, rare tumor subtypes including soft tumor sarcoma (STS) provide unique challenges for developing robust treatment data. By developing human based in vitro models, we can investigate potential therapeutic mechanisms for STS. Fibrosarcoma is one distinct histologic STS subtype that relies heavily on anthracycline treatment in the first line setting, however, there are limited options once resistance develops. Anthracyclines, including doxorubicin, exert their effect through a variety of mechanisms including reactive oxygen species, DNA-adduct formation, and inhibiting topoisomerase II, histone eviction, calcium and iron homeostasis, and ceramide overproduction. However, there have also been multiple mechanisms of doxorubicin resistance including disruption of cell membrane, alteration of cell surface molecules, inactivation of drugs, gene amplification, activating alternative signaling pathways, and affecting cellular repair mechanisms. In order to investigate the role of anthracycline resistance in fibrosarcoma lines we acquired two human derived fibrosarcoma lines SW684 and HT-1080 from American Type Culture Collection (ATCC). Characterization of HT-1080 using publicly available datasets demonstrated that TP53, CDK2NA and NF1 serve as major driver mutations while SW684 relies on NRAS and IDH1 mutations. We further characterized these cell lines in vitro and noted that HT-1080 has a quick doubling time of 16 hours while SW684 has a doubling time of 91 hours. Additionally, after doxorubicin treatment, we found that HT-1080 is sensitive with an IC50 of 5.594 nanomolar while SW684 is relatively doxorubicin resistant with an IC50 of 28.915 micromolar. While proliferative rate may play a role in the sensitivities of these cell lines further characterization of the mechanism leading to doxorubicin resistance is needed. To that end, we are using a CRISPR-Cas9 approach for further genome wide screening of these fibrosarcoma lines in the presence of doxorubicin. Exploring the genetic mechanisms that result in development of doxorubicin resistance may reveal novel, targetable mechanisms expanding treatment durability in this rare STS. Citation Format: Rodney Dixon Dorand, Donna Dang, Elizabeth J. Davis, Ben Ho Park. Investigating doxorubicin resistance in fibrosarcoma [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 3974.