Inhibition of BAD-Ser99 phosphorylation synergizes with PARP inhibition to ablate PTEN-deficient endometrial

Related Experiment Video

Updated: Sep 7, 2025

Non-Invasive Ultrasound Assessment of Endometrial Cancer Progression in Pax8-Directed Deletion of the Tumor Suppressors Arid1a and Pten in Mice
07:44

Non-Invasive Ultrasound Assessment of Endometrial Cancer Progression in Pax8-Directed Deletion of the Tumor Suppressors Arid1a and Pten in Mice

Published on: February 17, 2023

1.7K

Xi Zhang1,2, Peng Huang2, Liqiong Wang3

  • 1Shenzhen Bay Laboratory, Shenzhen, 518055, Guangdong, China.

Cell Death & Disease
|June 20, 2022
PubMed

Insights

Loss of PTEN in endometrial cancer causes resistance to PARP inhibitors. Inhibiting BAD phosphorylation with NPB synergizes with PARP inhibitors, overcoming resistance and improving treatment efficacy in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Loss of phosphatase and tensin homolog (PTEN) in endometrial carcinoma (EC) impairs DNA repair, conferring sensitivity to poly (ADP-ribose) polymerase inhibitors (PARPis).
  • However, PTEN-deficient EC develops PARPi resistance due to hyperactivation of MAPK and PI3K/AKT/mTOR pathways, which are integrated by BCL-2-associated death promoter (BAD).

Purpose of the Study:

  • To investigate the role of BAD phosphorylation at Ser99 (BADS99) in PARPi resistance in PTEN-deficient EC.
  • To evaluate the therapeutic potential of combining a pharmacological inhibitor of pBADS99 phosphorylation (NPB) with PARPis in PTEN-deficient EC models.

Main Methods:

  • Assessed BADS99 phosphorylation levels in relation to PTEN status in EC cells.
  • Utilized NPB to inhibit pBADS99 phosphorylation and evaluated its effects alone and in combination with PARPis (Olaparib, Rucaparib, Talazoparib) in vitro and in 3D ex vivo cultures.
  • Employed CRISPR-Cas9 to delete PTEN in replete EC cells to assess combination therapy efficacy.
  • Tested the combined NPB-PARPi treatment in PTEN-deficient EC xenograft and patient-derived organoid models.

Main Results:

  • Increased BADS99 phosphorylation was significantly associated with PTEN-deficient EC.
  • NPB treatment synergized with PARPis, significantly enhancing PARPi efficacy (up to 60-fold reduction in IC50), reducing cell viability, foci formation, and growth in 3D cultures.
  • Combined NPB-PARPi treatment induced apoptosis, promoted DNA damage via homologous recombination impairment, and effectively suppressed tumor growth in xenograft and organoid models.

Conclusions:

  • Combined inhibition of BADS99 phosphorylation and PARP represents a promising therapeutic strategy for overcoming PARPi resistance in PTEN-deficient endometrial carcinoma.
  • This combination approach demonstrates significant preclinical efficacy, suggesting potential for improved treatment outcomes in recurrent EC patients.

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