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

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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+ prostate cancer cell lines and patient-derived xenografts models.

RESULTS:

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 ASCL1 and CEACAM5 to determine that ASCL1 can drive neuroendocrine reprogramming of prostate cancer which is associated with increased chromatin accessibility of the CEACAM5 core promoter and CEACAM5 expression. Labetuzumab govitecan induced DNA damage in CEACAM5+ prostate cancer cell lines and marked antitumor responses in CEACAM5+ CRPC xenograft models including chemotherapy-resistant NEPC.

CONCLUSIONS:

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.

• Authors: Diana C DeLucia, Thomas M Cardillo, Lisa Ang, Mark P Labrecque, Ailin Zhang, James E Hopkins, Navonil De Sarkar, Ilsa Coleman, Rui M Gil da Costa, Eva Corey, Lawrence D True, Michael C Haffner, Michael T Schweizer, Colm Morrissey, Peter S Nelson, John K Lee
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 27 Issue 3 Pg. 759-774 (02 01 2021) ISSN: 1557-3265 [Electronic] United States
• PMID: 33199493 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2020 American Association for Cancer Research.

Chemical References

• ASCL1 protein, human
• Antibodies, Monoclonal, Humanized
• Basic Helix-Loop-Helix Transcription Factors
• CEACAM5 protein, human
• Carcinoembryonic Antigen
• GPI-Linked Proteins
• labetuzumab govitecan

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology, therapeutic use)
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Carcinoembryonic Antigen (genetics)
• Carcinoma, Neuroendocrine (drug therapy, genetics, pathology)
• Cell Line, Tumor
• DNA Damage (drug effects)
• Drug Resistance, Neoplasm (drug effects, genetics)
• GPI-Linked Proteins (antagonists & inhibitors, genetics)
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Promoter Regions, Genetic
• Prostate (pathology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, genetics, pathology)
• RNA-Seq
• Xenograft Model Antitumor Assays