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PTEN neddylation aggravates CDK4/6 inhibitor resistance in breast cancer

Fan Liu1,2, Weixiao Liu1,2, Yawen Tan3

  • 1Department of Cell Biology, Laboratory for Clinical Medicine, Capital Medical University, Beijing, 100069, China.

Oncogene
|June 18, 2025
PubMed

Insights

Targeting PTEN neddylation, which inactivates tumor suppressors and drives breast cancer, can overcome resistance to palbociclib. Echinacoside inhibits PTEN neddylation, restoring tumor suppression and enhancing treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • PTEN is a key tumor suppressor regulating the PI3K/Akt pathway.
  • PTEN inactivation via neddylation promotes breast cancer progression.
  • Drug resistance, particularly to CDK4/6 inhibitors like palbociclib, is a major clinical challenge.

Purpose of the Study:

  • To investigate the role of PTEN neddylation in palbociclib resistance in breast cancer.
  • To identify mechanisms linking PTEN neddylation to drug resistance.
  • To explore therapeutic strategies targeting PTEN neddylation.

Main Methods:

  • Assessed PTEN neddylation levels in relation to palbociclib resistance.
  • Investigated the impact of PTEN neddylation on PI3K/Akt and AP-1 signaling.
  • Examined the interaction between PTEN neddylation, JUND, and ITCH.
  • Identified Echinacoside as a PTEN neddylation inhibitor using in vitro and in vivo models.
  • Evaluated combination therapy with Echinacoside and palbociclib.

Main Results:

  • Elevated PTEN neddylation correlates with palbociclib resistance in breast cancer.
  • PTEN neddylation activates PI3K/Akt signaling and enhances AP-1 transcription factor activity.
  • PTEN neddylation stabilizes JUND by inhibiting its interaction with the E3 ligase ITCH.
  • Echinacoside inhibits PTEN neddylation by disrupting its interaction with XIAP.
  • Combination therapy with Echinacoside and palbociclib overcame drug resistance in preclinical models.

Conclusions:

  • PTEN neddylation is a critical mechanism driving palbociclib resistance in breast cancer.
  • Targeting PTEN neddylation, for example with Echinacoside, offers a novel strategy to restore tumor suppressor function.
  • Combination therapy holds promise for overcoming resistance and improving treatment outcomes for breast cancer patients.

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