Abstract 2210 To Die or Not to Die: Controlling Death in Breast and Ovarian Cancer Cells with a Novel Pathway Regulating Anticancer Drug

Using both orthotopic mouse and patient-derived xenograft models, our non-competitive anticancer drug ErSO induces complete or near-complete regression of advanced ERα+ breast and ovarian cancers. Unlike most cancer drugs, ErSO kills cells via necrosis pathway, a type of cell death that releases Damage Associated Molecular Pattern (DAMPs) from lysed cells and subsequently activates an innate immune response. This ErSO-induced pathway can eradicate deadly metastatic cancers without the resistance seen in modern-day endocrine therapy such as Tamoxifen and Fulvestrant. Mechanistically, ErSO works through ERα to instigate lethal hyperactivation of the anticipatory Unfolded Protein Response (a-UPR), resulting in protein synthesis inhibition, ATP depletion, and cell swelling, followed by membrane rupture. However, the specifics of ErSO-induced cell death were elusive. From a genome-wide CRISPR/Cas9 screening with negative selection against ErSO, the little-studied guanine exchange factor (GEF) FGD3 was identified as a top target. We show that FGD3 knockout protects breast cancer cells from ErSO-induced cell death, which increases the chance of recurrence after removing the treatment. Interestingly, instead of regulating upstream signals in the necrosis pathway, FGD3 regulates actin reorganization to mediate membrane rupture. This indicates that such cytoskeleton regulation plays a critical role in life-death situations, and it becomes relevant to understanding drug sensitivity in relation to FGD3 protein levels in the future when cancer patients are treated with ErSO or its derivatives. This research was supported and funded by the School of Molecular and Cellular Biology Summer Undergraduate Research Fellowship at the University of Illinois at Urbana-Champaign.