Data from Regulation of CEACAM5 and Therapeutic Efficacy of an Anti-CEACAM5–SN38 Antibody–drug Conjugate in Neuroendocrine Prostate Cancer

Abstract

<div>AbstractPurpose:<p>Neuroendocrine prostate cancer (NEPC) is an aggressive form of castration-resistant prostate cancer (CRPC) for which effective therapies are lacking. We previously identified carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) as a promising NEPC cell surface antigen. Here we investigated the scope of CEACAM5 expression in end-stage prostate cancer, the basis for CEACAM5 enrichment in NEPC, and the therapeutic potential of the CEACAM5 antibody–drug conjugate labetuzumab govitecan in prostate cancer.</p>Experimental Design:<p>The expression of CEACAM5 and other clinically relevant antigens was characterized by multiplex immunofluorescence of a tissue microarray comprising metastatic tumors from 34 lethal metastatic CRPC (mCRPC) cases. A genetically defined neuroendocrine transdifferentiation assay of prostate cancer was developed to evaluate mechanisms of CEACAM5 regulation in NEPC. The specificity and efficacy of labetuzumab govitecan was determined in CEACAM5<sup>+</sup> prostate cancer cell lines and patient-derived xenografts models.</p>Results:<p>CEACAM5 expression was enriched in NEPC compared with other mCRPC subtypes and minimally overlapped with prostate-specific membrane antigen, prostate stem cell antigen, and trophoblast cell surface antigen 2 expression. We focused on a correlation between the expression of the pioneer transcription factor <i>ASCL1</i> and <i>CEACAM5</i> to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the <i>CEACAM5</i> core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5<sup>+</sup> prostate cancer cell lines and marked antitumor responses in CEACAM5<sup>+</sup> CRPC xenograft models including chemotherapy-resistant NEPC.</p>Conclusions:<p>Our findings provide insights into the scope and regulation of CEACAM5 expression in prostate cancer and strong support for clinical studies of labetuzumab govitecan for NEPC.</p></div>