LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate
Abstract:
Lysine-specific demethylase 1 (LSD1 or KDM1A ) has emerged as a critical mediator of tumor progression in metastatic castration-resistant prostate cancer (mCRPC). Among mCRPC subtypes, neuroendocrine prostate cancer (NEPC) is an exceptionally aggressive variant driven by lineage plasticity, an adaptive resistance mechanism to androgen receptor axis-targeted therapies. Our study shows that LSD1 expression is elevated in NEPC and associated with unfavorable clinical outcomes. Using genetic approaches, we validated the on-target effects of LSD1 inhibition across various models. We investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor with low nanomolar potency. Our findings demonstrate potent antitumor activity against CRPC models, including tumor regressions in NEPC patient-derived xenografts. Mechanistically, our study uncovers that LSD1 inhibition suppresses the neuronal transcriptional program by downregulating ASCL1 through disrupting LSD1:INSM1 interactions and de-repressing YAP1 silencing. Our data support the clinical development of LSD1 inhibitors for treating CRPC - especially the aggressive NE phenotype.
Statement Of Significance:
Neuroendocrine prostate cancer presents a clinical challenge due to the lack of effective treatments. Our research demonstrates that bomedemstat, a potent and selective LSD1 inhibitor, effectively combats neuroendocrine prostate cancer by downregulating the ASCL1- dependent NE transcriptional program and re-expressing YAP1.
Insights
Lysine-specific demethylase 1 (LSD1) inhibition shows promise for aggressive neuroendocrine prostate cancer. Bomedemstat, an LSD1 inhibitor, demonstrated significant antitumor activity in preclinical models, offering a new therapeutic avenue.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) progression is linked to Lysine-specific demethylase 1 (LSD1/KDM1A).
- Neuroendocrine prostate cancer (NEPC), an aggressive mCRPC subtype, is driven by lineage plasticity and lacks effective treatments.
- Elevated LSD1 expression in NEPC correlates with poor clinical outcomes.
Approach:
- Validated on-target effects of LSD1 inhibition using genetic models.
- Investigated the therapeutic potential of bomedemstat, an orally bioavailable, irreversible LSD1 inhibitor.
- Assessed bomedemstat's efficacy in CRPC and NEPC patient-derived xenograft models.
Key Points:
- Bomedemstat exhibited potent antitumor activity against CRPC models, including significant tumor regressions in NEPC xenografts.
- LSD1 inhibition suppresses the NE transcriptional program by downregulating ASCL1 via disrupted LSD1:INSM1 interactions.
- LSD1 inhibition leads to the de-repression of YAP1 silencing.
Conclusions:
- LSD1 inhibition is a viable therapeutic strategy for mCRPC, particularly for the aggressive NEPC subtype.
- Bomedemstat demonstrates significant potential for clinical development in treating NEPC.
- Targeting LSD1 offers a novel approach to overcome therapeutic resistance in prostate cancer.
