Prostate-Specific Membrane Antigen Expression and Response to DNA Damaging Agents in Prostate Cancer.
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Authors
Sheehan, B
Neeb, A
Buroni, L
Paschalis, A
Riisnaes, R
Gurel, B
Gil, V
Miranda, S
Crespo, M
Guo, C
Jiménez Vacas, J
Figueiredo, I
Ferreira, A
Welti, J
Yuan, W
Carreira, S
Sharp, A
de Bono, J
Neeb, A
Buroni, L
Paschalis, A
Riisnaes, R
Gurel, B
Gil, V
Miranda, S
Crespo, M
Guo, C
Jiménez Vacas, J
Figueiredo, I
Ferreira, A
Welti, J
Yuan, W
Carreira, S
Sharp, A
de Bono, J
Document Type
Journal Article
Date
2022-07-15
Date Accepted
2022-05-09
Abstract
PURPOSE: Prostate-specific membrane antigen (PSMA) targeting therapies such as Lutetium-177 (177Lu)-PSMA-617 are affecting outcomes from metastatic castration-resistant prostate cancer (mCRPC). However, a significant subset of patients have prostate cancer cells lacking PSMA expression, raising concerns about treatment resistance attributable at least in part to heterogeneous PSMA expression. We have previously demonstrated an association between high PSMA expression and DNA damage repair defects in mCRPC biopsies and therefore hypothesized that DNA damage upregulates PSMA expression. EXPERIMENTAL DESIGN: To test this relationship between PSMA and DNA damage we conducted a screen of 147 anticancer agents (NCI/NIH FDA-approved anticancer "Oncology Set") and treated tumor cells with repeated ionizing irradiation. RESULTS: The topoisomerase-2 inhibitors, daunorubicin and mitoxantrone, were identified from the screen to upregulate PSMA protein expression in castration-resistant LNCaP95 cells; this result was validated in vitro in LNCaP, LNCaP95, and 22Rv1 cell lines and in vivo using an mCRPC patient-derived xenograft model CP286 identified to have heterogeneous PSMA expression. As double-strand DNA break induction by topoisomerase-2 inhibitors upregulated PSMA, we next studied the impact of ionizing radiation on PSMA expression; this also upregulated PSMA protein expression in a dose-dependent fashion. CONCLUSIONS: The results presented herein are the first, to our knowledge, to demonstrate that PSMA is upregulated in response to double-strand DNA damage by anticancer treatment. These data support the study of rational combinations that maximize the antitumor activity of PSMA-targeted therapeutic strategies by upregulating PSMA.
Citation
Clinical Cancer Research, 2022, 28 (14), pp. 3104 - 3115
Source Title
Clinical Cancer Research
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
1557-3265
1557-3265
Collections
Research Team
Cancer Biomarkers
PrCa Targeted Therapy
Translational Therapeutic
PrCa Targeted Therapy
Translational Therapeutic