# ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer

> **NIH NIH R01** · CEDARS-SINAI MEDICAL CENTER · 2022 · $1

## Abstract

PROJECT SUMMARY
 Metastatic prostate cancer (mPCa) is incurable and responsible for the majority of PC associated mortality.
Therefore, there is a critical need to identify drivers of mPCa to enable early identification and interceptive
therapeutic strategies to provide durable responses in patients. Androgen deprivation therapy (ADT) is the
primary line of treatment for mPCa. ADT initially extends survival but is not curative as the patient’s tumor
acquires castration resistance (mCRPC). A majority of mCRPC remain dependent on the function of the androgen
receptor (AR), though due to the inclusion of more potent AR antagonist (eg: enzalutamide) has led to the
emergence, in a subset of cases (approximately 20%), of resistance mechanisms independent of AR activity
(CRPC-AI). CRPC-AI adapt to ADT via lineage plasticity rather than a result of resistant mutations, adopting a
phenotype no longer reliant on AR expression and signaling. These tumors may display neuroendocrine features,
a stem or basal cell-like phenotype, altered kinase signaling, and characteristic epigenetic alterations. Recently,
we and others have characterized the molecular landscape of CRPC-AI and have identified and validated new
therapeutic targets and drivers, including loss of Retinoblastoma-1 (RB) and TP53, and induction of specific
epigenetic/reprogramming factors such as (Enhancer of Zeste Homolog 2) EZH2 and SOX2.
 Additionally, our work validated the importance of EZH2 reprogramming downstream of RB1 loss, driving
lineage plasticity and resistance to ADT. Moreover, inhibition of EZH2 enabled lineage reversal and re-sensitized
RB loss prostate cancer to ADT. Importantly, recent data from patients with mCRPC identified RB genetic
aberrations as the strongest predictor of poor outcome. These data implicate RB as a dominant molecular
mechanism driving lethal prostate cancer. Currently there is no therapeutic option to provide durable
response in patients with RB loss-of-function (LOF). Therefore, there is a critical need to delineate
downstream effectors of RB LOF so that therapeutic targets can be identified and validated in clinical
trials. Specific to this application, our functional genomic screen has identified dependence on DNA damage
repair kinases – specifically – ATR. This proposed work is innovative because it will provide deeper mechanistic
knowledge of drivers of RB deficient prostate cancer and therapeutic options towards a currently untreatable
phenotype. Through this work we will validate the ability of DDR kinase targeting to exacerbate DDR deficiency
and to generate hypersensitivity in RB-deficient prostate models (Aim 1), determine the correlation between RB
function, HR proficiency and response to M6620+carboplatin and docetaxel+carboplatin in preclinical models
and clinical samples (Aim 2), and evaluate synergy of ATR kinase inhibition, EZH2 inhibition, and immune
checkpoint blockade therapy in pre-clinical RB-deficient prostate mouse models (Aim 3). Ulti...

## Key facts

- **NIH application ID:** 10472549
- **Project number:** 5R01CA252468-04
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Leigh Ellis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1
- **Award type:** 5
- **Project period:** 2020-06-08 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10472549

## Citation

> US National Institutes of Health, RePORTER application 10472549, ATR Dependency as a Novel Therapeutic Target in Lethal RB Deficient ProstateCancer (5R01CA252468-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10472549. Licensed CC0.

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