Biology subjects

Sun, N.-Y.

Publications and source records attributed to Sun, N.-Y..

2 recordsLinked to original sources

bioRxiv2026

Estradiol Modulates Cytotoxic Responses to Topoisomerase II Targeting Agents in Estrogen Receptor Positive Breast Cancer Cells

Endocrine therapy is the primary treatment for estrogen receptor-positive (ER+) breast cancer. Paradoxically high dose estradiol can induce ER+ breast cancer cell death in an ER dependent manner. Although a well-established phenomenon, the mechanism of estradiol (E2)-induced breast cancer cell death has remained elusive. More recent evidence has revealed that E2 drives estrogen receptor alpha (ERa)-dependent transcription through TOP2 mediated DNA double-strand breaks. This raises two important questions. Firstly, is E2-dependent breast cancer cell death dependent on TOP2 mediated DNA double strand cleavage, and, secondly, does E2 signaling alter sensitivity of ER+ breast cancer cells to TOP2 poisons. Two ER+ breast cancer cell lines T47D and MCF-7 cells were treated with E2, doxorubicin (TOP2 poison) or T638 (catalytic TOP2 inhibitor), alone, and with each drug combined with E2 for 72 h. Viability was measured and normalized to untreated controls and IC50 values were calculated from dose-response curve. E2 enhanced doxorubicin potency in T47D and MCF7 ER+ breast cancer cell lines. E2 was toxic to T47D and MCF7 cells in a concentration dependent manner. The TOP2 catalytic inhibitor, T638, which blocks TOP2-mediated DNA cleavage reduced viability of both cell lines when used alone but decreased the cytotoxic effects of E2 about 7.6-fold, consistent with a role for TOP2-mediated DNA cleavage in the cytotoxic effects of E2. Thus, E2 sensitizes ER+ breast cancer cells to the TOP2 poison, whereas T638, the catalytic inhibitor, diminishes the cytotoxic response to E2. These opposing effects are consistent with E2 acting through TOP2-dependent DNA breaks.

cancer biology↗

bioRxiv2024

Identification of DLK1, a Notch ligand, as an immunotherapeutic target and regulator of tumor cell plasticity and chemoresistance in adrenocortical carcinoma

Immunotherapeutic targeting of cell surface proteins is an increasingly effective cancer therapy. However, given the limited number of current targets, the identification of new surface proteins, particularly those with biological importance, is critical. Here, we uncover delta-like non-canonical Notch ligand 1 (DLK1) as a cell surface protein with limited normal tissue expression and high expression in multiple refractory adult metastatic cancers including small cell lung cancer (SCLC) and adrenocortical carcinoma (ACC), a rare cancer with few effective therapies. In ACC, ADCT-701, a DLK1 targeting antibody-drug conjugate (ADC), shows potent in vitro activity among established cell lines and a new cohort of patient-derived organoids as well as robust in vivo anti-tumor responses in cell line-derived and patient-derived xenografts. However, ADCT-701 efficacy is overall limited in ACC due to high expression and activity of the drug efflux protein ABCB1 (MDR1, P-glycoprotein). In contrast, ADCT-701 is extremely potent and induces complete responses in DLK1+ ACC and SCLC in vivo models with low or no ABCB1 expression. Genetic deletion of DLK1 in ACC dramatically downregulates ABCB1 and increases ADC payload and chemotherapy sensitivity through NOTCH1-mediated adrenocortical de-differentiation. Single cell RNA-seq of ACC metastatic tumors reveals significantly decreased adrenocortical differentiation in DLK low or negative cells compared to DLK1 positive cells. This works identifies DLK1 as a novel immunotherapeutic target that regulates tumor cell plasticity and chemoresistance in ACC. Our data support targeting DLK1 with an ADC in ACC and neuroendocrine neoplasms in an active first-in-human phase I clinical trial (NCT06041516).

cancer biology↗