# Novel roles of IGFBP3 in Olaparib resistance in advanced prostate cancer

> **NIH VA I01** · VA NORTHERN CALIFORNIA HEALTH CARE SYS · 2024 · —

## Abstract

Abstract
Mortality from advanced prostate cancer remains a significant challenge facing clinicians due to the
incurable nature of the disease. PARP inhibition (PARPi) is a novel strategy for the treatment of prostate
cancer which exploits synthetic lethality by specifically targeting tumor cells which harbor DNA damage
repair defects. PARPi, including Olaparib, represent the dawn of precision medicine for the treatment of
prostate cancer and the strategy was approved in 2020. Despite this tremendous step forward, resistance to
PARPi has already been clinically documented. We have developed novel PARPi resistant cell lines, LN-
OlapR and 2B-OlapR, derived from LNCaP and C4-2B prostate cancer cell lines respectively. Our published
and on-going studies demonstrate that PARPi’s induce DNA damage leading to p53 activation and
subsequently to either cell death (cleaved-PARP) or p21-dependent senescence. RNA-sequencing of our
OlapR models versus parental cells revealed a shared and significant increase in IGFBP3 expression.
Preliminary data confirm overexpression of IGFBP3 in OlapR cells versus parental cells and shows that
inhibition of IGFBP3 reduces OlapR cell viability, increases DNA damage, and promotes the efficacy of
PARP inhibition. Our preliminary data also show that relative to parental cells, OlapR cells express
significantly higher levels of phosphorylated EGFR and DNA-PKc. Targeting EGFR by either its specific
EGFR siRNA or the small molecule inhibitor Gefitinib overcame olaparib resistance. The overall hypothesis
is that overexpressed IGFBP3 mediates resistance by enhancing DNA repair through formation of a
tripartite complex with EGFR and DNA-PKc, and blocking this signaling pathway by inhibiting EGFR activity
with Gefitinib overcomes resistance to olaparib. The specific aims of this proposal are: 1. Define the role of
IGFBP3 towards promoting Olaparib resistance in resistant cells. 2. Determine if IGFBP3 promotes DNA
repair pathways in resistant cells. 3. Determine the anti-tumor response of targeting IGFBP3/EGFR in
combination with Olaparib. This proposal will address a significant unmet research need. We will study
novel models of PARPi resistance which will allow us to characterize mechanisms mediating PARPi
sensitivity. We will demonstrate the role of IGFBP3 as a key mediator of resistance and we will explore
novel therapeutic strategies which may be developed for clinical impact.

## Key facts

- **NIH application ID:** 10793831
- **Project number:** 1I01BX006198-01A1
- **Recipient organization:** VA NORTHERN CALIFORNIA HEALTH CARE SYS
- **Principal Investigator:** Allen C. Gao
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2024-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10793831

## Citation

> US National Institutes of Health, RePORTER application 10793831, Novel roles of IGFBP3 in Olaparib resistance in advanced prostate cancer (1I01BX006198-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10793831. Licensed CC0.

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