ORY‐1001, a KDM1A inhibitor, inhibits proliferation, and promotes apoptosis of triple negative breast cancer cells by inactivating androgen receptor

Abstract

Breast cancer (BC), which is widely considered as the most common cancer in women around the world, evokes ~1.7 million new BC cases and 522,000 BC‐related deaths each year. Triple negative breast cancer (TNBC) is clinically confirmed as one of the most aggressive subtypes of BC. ORY‐1001, a clinically used lysine specific demethylase 1 (LSD1/KDM1A) inhibitor, was investigated herein to confirm its role in the progression of TNBC and reveal the potential mechanism. After treatment with ORY‐1001 in MDA‐MB‐231 and BT549 cells, the cell proliferation and apoptosis were respectively measured by CCK‐8 and TUNEL assays. The expression of proliferation‐ and apoptosis‐associated proteins was tested by means of western blot analysis. Then, R1881, an androgen receptor (AR) agonist, was used to evaluate whether the effects of ORY‐1001 on proliferation and apoptosis of TNBC cells was mediated by regulating AR. Results indicated that ORY‐1001 treatment restrained the proliferation while enhanced the apoptosis of BC cells, accompanied by the change of proliferation‐ and apoptosis‐related proteins expression. Furthermore, ORY‐1001 reduced the level of AR in BC cells. After the activation of AR by R1881, the decreased proliferation and enhanced apoptosis of BC cells triggered by ORY‐1001 intervention were partially abolished. In conclusion, this paper has presented the first evidence to suggest that ORY‐1001 inhibits proliferation and promotes apoptosis of TNBC cells by suppressing AR expression, which may constitute the theoretical basis for the clinical use of ORY‐1001 in the treatment of this disease.

Computational Pipeline to Identify Gene signatures that Define Cancer Subtypes

“…Upon further validation, these targets can lead to new treatment options for aggressive breast cancer subtypes such as Triple negative breast cancer. Similarly, many identified genes, such as KDM1A in astrocytoma, MMP3 (Bufu, et al, 2018) in glioblastoma, and PSEN1 in oligodendroglioma, have previously been correlated with cancer (Feng, et al, 2022; Xu, et al, 2018; Zhang, et al, 2022). These 3 genes also have inhibitors available, such as ladademstat, which can potentially target KDM1A (LSD1) (Salamero, et al, 2020), thus can be used to inhibit the growth of astrocytoma glioma.…”

“…FOXA1 can possibly be targeted to inhibit the growth of Triple negative breast cancer (Calissi, et al, 2021). miRNA-214 can be used to target MCM5 and potentially inhibit the growth of Luminal A (Wang, et al, 2022) and miR-601 can be used to target KRT5 to inhibit Luminal B progression (Du et al, 2019). These genes can potentially serve as biomarkers for cancer subtype identification and treatments for personalized therapy.…”

A state-of-the-art review on LSD1 and its inhibitors in breast cancer: Molecular mechanisms and therapeutic significance

“…Mounting evidence supports that LSD1 is overexpressed in many subtypes of BC and promotes their proliferation (Pollock et al, 2012;Yang et al, 2018d;Xu et al, 2019;Wang et al, 2022), differentiation (Wu et al, 2013;Zhang et al, 2013;Ji et al, 2021), metastasis (Li et al, 2011;Qiu et al, 2018;Zheng et al, 2018;Hu et al, 2019;Gong et al, 2021), and drug resistance (Bennani-Baiti, 2012;Verigos et al, 2019;Zhou et al, 2021a;Liu et al, 2022), which makes LSD1 become a promising target for BC therapy. But the detailed mechanisms of the LSD1 in BC progression are unclear and more potential anti-tumor pathways or downstream genes are yet to clarify due to the heterogeneity of varieties of BC subtypes.…”

“…NCD38 (6), a selective LSD1 inactivator optimized from PCPA with IC 50 of 0.59 μM (Sugino et al, 2017), could reduce the stemness of TNBC cells and tumor growth in vitro (Zhou et al, 2021a). ORY-1001 (7), a PCPA derivative in phase II clinical trial for acute myelocytic leukemia, could inhibit TNBC cells and HER2-positive BC cells in distinct mechanisms (Figure 4) (Cuyàs et al, 2020;Wang et al, 2022). Compound 7 inhibited HER2-positive BC via reducing SOX2-driven breast cancer stem cells.…”

“…In the mechanism, compound 7 disturbed the assembly between LSD1 and co-repressor RCOR1/ CoREST via blocking the binding between LSD1 and FAD cofactor, and thus enhanced transcriptional repression of SOX2 (Cuyàs et al, 2020). In TNBC, compound 7 suppressed the proliferation of TNBC cells via devitalizing androgen receptor (Wang et al, 2022).…”