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Rosen, D. M.

Publications and source records attributed to Rosen, D. M..

2 recordsLinked to original sources
bioRxiv2024

LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer

Progression to lethal metastatic castration-resistant prostate cancer (mCRPC) is driven in part by epigenetic modulators such as LSD1 (KDM1A), a lysine-specific demethylase. Yet, mCRPC is increasingly recognized as a highly heterogeneous disease whose classification into subtypes is defined by the extent of androgen receptor (AR) and/or neuroendocrine (NE) characteristics. Meanwhile, the role of LSD1 in driving the different subtypes of mCRPC has remained unclear. Here, we assess the necessity of LSD1 in driving progression of mCRPC subtypes including AR+/NE- (ARPC), AR-/NE+ (NEPC), AR+/NE+ (amphicrine; AMPC), and AR-/NE- (double-negative; DNPC) through the use of LSD1 inhibitors in clinical development. LSD1 inhibition (LSD1i) was observed to be highly effective in restricting growth of NEPC, and efficacy was associated with TP53 loss-of-function. Mice bearing NEPC patient-derived xenografts treated with the LSD1 inhibitors, bomedemstat (MK-3543) or iadademstat (ORY-1001), exhibited suppression of the NE transcriptional profile, including ASCL1. LSD1i also induced expression and activity of YAP1, a non-NE transcription factor canonically silenced in NEPC (YAPOFF cancer), thereby switching NEPC from a YAPOFF to a YAPON cancer class. Therapeutically-induced YAPON NEPC tumors exhibited cell cycle arrest and repression of proliferative transcriptional programs. Importantly, the LSD1i-mediated YAPON state induced sensitivity to an inhibitor of YAP/TEAD function, IAG933, which extended antitumor efficacy against NEPC. Altogether, these findings indicate that patients diagnosed with NEPC may obtain greater relative benefit from LSD1-targeted therapies compared to those with other mCRPC subtypes and that dual inhibition of LSD1 and YAP/TEAD function demonstrates a promising treatment strategy potentially extending to other YAPOFF cancers. SignificanceAcross prostate cancer subtypes, NEPC is exceptionally responsive to LSD1 inhibition and this response is enhanced in combination with a YAP/TEAD disruptor which may improve patient selection and outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/576106v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@77332eorg.highwire.dtl.DTLVardef@1c127d0org.highwire.dtl.DTLVardef@1cec77org.highwire.dtl.DTLVardef@e87ed7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗
bioRxiv2021

Aldehyde dehydrogenase 3A1 deficiency leads to mitochondrial dysfunction and impacts salivary gland stem cell self-renewal, differentiation and survival

Adult salivary stem/progenitor cells (SSPC) have an intrinsic property to self-renew in order to maintain tissue architecture and homeostasis. Adult salivary glands have been documented to harbor SSPC, which have been shown to play a vital role in the regeneration of the glandular structures post radiation damage. We have previously demonstrated that activation of aldehyde dehydrogenase 3A1 (ALDH3A1) after radiation reduced aldehyde accumulation in SSPC, leading to less apoptosis and improved salivary function. We subsequently found that sustained pharmacological ALDH3A1 activation is critical to enhance regeneration of murine submandibular gland after radiation damage. Further investigation shows that ALDH3A1 function is crucial for SSPC self-renewal and differentiation even in the absence of radiation stress. Salivary glands from Aldh3a1-null mice have fewer acinar structures than wildtype mice. ALDH3A1 deletion or pharmacological inhibition in SSPC leads to a decrease in mitochondrial DNA copy number, lower expression of mitochondrial specific genes and proteins, structural abnormalities, lower membrane potential, and reduced cellular respiration. Loss or inhibition of ALDH3A1 also elevates ROS levels and accumulation of ALDH3A1 substrate 4-hydroxynonenal (4-HNE, a lipid peroxidation product), leading to decreased survival of murine SSPC that can be rescued by treatment with 4-HNE specific carbonyl scavengers. Our data indicate that ALDH3A1 activity protects mitochondrial function and is important for the development and regeneration activity of SSPC. This knowledge will help to guide our translational strategy of applying ALDH3A1 activators in the clinic to prevent radiation-related hyposalivation in head and neck cancer patients.

cell biology↗