NSD2 inhibition as a therapeutic approach for treatment-induced neuroendocrine prostate cancer.

198 Background: Trans-differentiation from adenocarcinoma to neuroendocrine histology is a major treatment-induced resistance mechanism against androgen receptor pathway inhibitors (ARPI) in castration-resistant prostate cancer (CRPC). With increased use of ARPI in the clinic, neuroendocrine prostate cancer (NEPC) constitutes 15~20% of CRPC. The histone H3 K36 di-methyltransferase NSD2 has recently been shown to be a driver of the adeno-to-neuroendocrine trans-differentiation. The level of NSD2 expression is markedly increased in AR(-) NEPC compared to AR(+) CRPC and correlates with a poor disease outcome. Furthermore, genetic depletion of NSD2 has been shown to reverse AR(-) NEPC to an AR(+) adenocarcinoma phenotype and re-sensitize the prostate cancer cells to enzalutamide treatment. Methods: K36 Therapeutics has developed a selective NSD2 inhibitor KTX1001 that is currently undergoing clinical evaluation in multiple myeloma (NCT05651932). Dose proportional pharmacokinetics and on-target pharmacodynamics of KTX1001 have been observed as well as an excellent safety profile in patients. Here we have investigated whether pharmacological inhibition of NSD2 reverses AR(-) NEPC to AR(+) adenocarcinoma in preclinical models. Results: In the NEPC cell line NCI-H660, KTX1001 treatment led to a significant change in the epigenome landscape, resulting in reduced expression of neuroendocrine markers SYP, CHGA and FOXA2 and concomitant upregulation of the adenocarcinoma markers AR, NKX3.1 and KLK3. These observations are consistent with a lineage change from AR(-) NEPC to AR(+) adenocarcinoma. We further investigate this in vivo using a NEPC patient-derived xenograft model. Indeed, treatment with our selective NSD2 inhibitor resulted in pronounced upregulation of the Hallmark Androgen Response gene signature, suggesting restoration of the AR-signaling pathway. Moreover, Hallmark E2F and Myc signatures, which are known to be elevated in NEPC cells, were markedly downregulated after NSD2 inhibitor treatment. These observations suggest a significant change in NEPC lineage identity towards AR(+) adenocarcinoma. Conclusions: These data support our hypothesis that NSD2 inhibition can reverse NEPC to AR(+) adenocarcinoma lineage and restore sensitivity to standard-of-care ARPI. Given these mechanistic insights and the safety profile observed with our NSD2 inhibitor in the clinic, evaluation of NSD2 inhibition in NEPC patients is warranted.