# Defining PARP Inhibitor Response and Resistance in Prostate Cancer

> **NIH NIH K01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $166,536

## Abstract

PROJECT SUMMARY/ABSTRACT
The objective of this K01 award is to promote the development of Dr. Alan Lombard into an independent
prostate cancer researcher. The proposed project will expand understanding of PARP inhibition for the
treatment of prostate cancer and position Dr. Lombard, the principal investigator, to launch an independent line
of study. Furthermore, intense mentoring and focused training goals are described to facilitate Dr. Lombard's
transition from mentee to independent investigator. Advanced prostate cancer remains an incurable disease.
PARP inhibitors (PARPi), such as rucaparib and olaparib, are an exciting new therapy recently approved for
the treatment of a subset of patients. It is thought that PARPi's function by causing DNA damage and
exacerbating homologous recombination deficiency to elicit synthetic lethality. While PARP inhibition promises
to significantly improve the management of prostate cancer patients, questions remain regarding their use
including 1) how do PARP inhibitor sensitive prostate tumor cells respond to treatment and 2) what
mechanisms will ultimately give rise to PARP inhibitor resistance. To address these questions, two olaparib
resistant prostate cancer models were developed, LN-OlapR and 2B-OlapR, using the PARPi sensitive LNCaP
and C4-2B cell lines, respectively. OlapR models exhibit robust resistance to olaparib and cross-resistance to
other clinically relevant PARPi's. Preliminary data suggests that PARPi sensitive cells respond to treatment not
only through cell death but also through G2/M arrested, p21 dependent senescence, which may provide a
repository of surviving cells that evade PARPi cytotoxicity and give rise to resistance. PARPi induced
senescence leads to activation of the senescence associated secretory phenotype (SASP) which promotes
maintenance of senescence and cellular viability. Interestingly, OlapR cells 1) do not increase p21 expression,
2) do not G2/M arrest, and 3) blunt senescence in response to PARP inhibition, suggesting that resistance is
predicated upon cell cycle checkpoint override, which data suggests can be targeted through inhibition of
CDK1. The observations lead to the hypothesis that PARPi induced p21 dependent senescence is
overcome in resistance through cell cycle checkpoint override. In Aim 1, studies will determine whether
senescence is a general response to PARPi's and mechanistically define the importance of p21 in this
phenotype. In Aim 2, characterization of the PARPi induced SASP will be undertaken, with emphasis on
understanding the role of IGFBP3, a known SASP factor. Lastly, Aim 3 will further develop the strategy of
targeting CDK1 for the treatment of PARPi resistant prostate cancer and seek to understand how resistant
cells override the G2/M checkpoint. The environment at UC Davis is replete with all the resources, expertise,
and faculty needed to foster the development of Dr. Lombard and completion of proposed studies. Dr.
Lombard will undergo a numb...

## Key facts

- **NIH application ID:** 10440522
- **Project number:** 5K01CA262351-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Alan Lombard
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $166,536
- **Award type:** 5
- **Project period:** 2021-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10440522

## Citation

> US National Institutes of Health, RePORTER application 10440522, Defining PARP Inhibitor Response and Resistance in Prostate Cancer (5K01CA262351-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10440522. Licensed CC0.

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