Related Experiment Video

Updated: Jul 4, 2025

Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
09:40

Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer

Published on: August 2, 2024

2.6K

IGFBP3 promotes resistance to Olaparib via modulating EGFR signaling in advanced prostate cancer

Amy R Leslie1, Shu Ning1, Cameron M Armstrong1

  • 1Department of Urologic Surgery, University of California Davis, Davis, CA, USA.

Iscience
|February 8, 2024
PubMed

Insights

Insulin-like growth factor-binding protein 3 (IGFBP3) drives resistance to Olaparib in prostate cancer by enhancing DNA repair. Inhibiting IGFBP3 or EGFR restores Olaparib sensitivity, offering new therapeutic strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Olaparib, a PARP inhibitor (PARPi), treats prostate cancer with DNA repair defects.
  • Clinical resistance to Olaparib is a significant challenge in castration-resistant prostate cancer (CRPC).

Purpose of the Study:

  • To investigate the mechanisms of acquired Olaparib resistance in prostate cancer.
  • To identify potential therapeutic targets to overcome Olaparib resistance.

Main Methods:

  • Developed Olaparib-resistant (OlapR) prostate cancer cell lines (LNCaP, C4-2B).
  • Assessed Insulin-like growth factor-binding protein 3 (IGFBP3) expression in resistant models.
  • Investigated the role of IGFBP3, EGFR, and DNA-PKcs in DNA repair and Olaparib resistance.
  • Utilized gene silencing and EGFR inhibition (Gefitinib) to evaluate therapeutic strategies.

Main Results:

  • High IGFBP3 expression was observed in acquired and intrinsic Olaparib-resistant prostate cancer models.
  • IGFBP3 promotes Olaparib resistance by enhancing DNA repair via EGFR and DNA-PKcs activation.
  • IGFBP3 depletion resensitized resistant cells to Olaparib by increasing DNA damage and cell death.
  • EGFR inhibition mimicked IGFBP3 inhibition, reducing cell viability and restoring Olaparib sensitivity.

Conclusions:

  • IGFBP3 is a key mediator of Olaparib resistance in prostate cancer.
  • Targeting IGFBP3 or EGFR represents a promising strategy to overcome acquired resistance to Olaparib.
  • Combined inhibition of PARP and EGFR/IGFBP3 pathways may enhance treatment efficacy.
Keywords:
CancerCell biologyTranscriptomics

More Related Videos

An Orthotopic Murine Model of Human Prostate Cancer Metastasis06:48

An Orthotopic Murine Model of Human Prostate Cancer Metastasis

Published on: September 18, 2013

35.2K
Author Spotlight: Exploring the Role of FAM83A in Cervical Cancer04:20

Author Spotlight: Exploring the Role of FAM83A in Cervical Cancer

Published on: February 9, 2024

934

Related Concept Videos

Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.5K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
3.8K
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K
PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a...
3.6K
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.3K