Abstract 563: Targeting PDE4D reinstates toxic PARP trapping via cAMP-ROS-DNA damage axis and restores the efficacy of standard of care in treatment-refractory ER+ breast cancer

Abstract Endocrine therapies, modulating ER level and/or activity, and the CDK4/6 inhibitors are among the standard-of-care (SOC) therapies used in estrogen receptor-positive (ER+) breast cancer. However, most ER+ breast cancer patients eventually develop resistance to SOC, representing a major clinical challenge that reduces clinical outcome. Therefore, elucidating the common mechanisms of sensitivity and resistance to SOC therapies, and identifying novel actionable targets are urgently needed. Here, we demonstrated that cell death induced by endocrine therapies and CDK4/6 inhibitors involves toxic PARP1 trapping and generation of a functional BRCAness (i. e. , BRCA1/2 deficiency) phenotype, leading to transcriptional blockage. We showed that this is achieved by activation of the cAMP/reactive oxygen species (ROS) /DNA damage axis upon downregulation of phosphodiesterase 4D (PDE4D). Importantly, we identified PDE4D as a novel ER target gene that in turn stimulates ER activity in a feedforward loop in endocrine-responsive models. However, during SOC resistance, an ER-to-EGFR switch induces PDE4D overexpression via c-Jun. Inhibition of PDE4D using BPN14770, the first-in-class PDE4D allosteric inhibitor that has successfully completed Phase II trials in Fragile X syndrome, reinstates PARP1 trapping and BRCAness, leading to drug sensitization in vitro and in vivo. Furthermore, inhibition of EGFR or PARP1 recapitulates the effects of PDE4D targeting and overcomes SOC resistance irrespective of the BRCA1/2 status in cell line models, primary cultures and organoids of endocrine resistant ER+ PDXs. Notably, we demonstrated that high PDE4D mRNA and protein expression is associated with dramatically worse disease-free survival and overall survival in endocrine therapy-treated ER+ breast cancer. Given the availability of potent and non-toxic PDE4D inhibitors, and clinically approved EGFR and PARP1 inhibitors, our findings have great translational potential to improve the clinical outcome of refractory ER+ breast cancers. Citation Format: Ozge Saatci, Metin Cetin, Meral Uner, Unal M. Tokat, Ioulia Chatzistamou, Elodie Montaudon, Aytekin Akyol, Sercan Aksoy, Aysegul Uner, Elisabetta Marangoni, Mathew Sajish, Ozgur Sahin. Targeting PDE4D reinstates toxic PARP trapping via cAMP-ROS-DNA damage axis and restores the efficacy of standard of care in treatment-refractory ER+ breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 563.