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HER2 Mediates PSMA/mGluR1-Driven Resistance to the DS-7423 Dual PI3K/mTOR Inhibitor in PTEN Wild-type Prostate Cancer

Valentí Gómez1, Myria Galazi1, Gregory Weitsman2

  • 1UCL Cancer Institute, University College London, London, United Kingdom.

Molecular Cancer Therapeutics
|January 28, 2022
PubMed

Insights

Targeting PI3K/mTOR in PTEN wild-type prostate cancer shows resistance. Combining PI3K/mTOR inhibitors with HER2 or mGluR1 inhibitors offers a new therapeutic strategy for this challenging cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Prostate cancer is a leading cause of male mortality.
  • PI3K/AKT/mTOR pathway alterations drive prostate cancer progression, particularly PTEN inactivation.
  • Current PI3K/AKT/mTOR inhibitors lack efficacy in PTEN wild-type prostate cancer, representing a clinical unmet need.

Purpose of the Study:

  • To investigate therapeutic strategies for PTEN wild-type prostate cancer using a dual PI3K/mTOR inhibitor.
  • To explore the efficacy of combining the PI3K/mTOR inhibitor DS-7423 with HER2 or mGluR1 inhibitors.
  • To understand resistance mechanisms in PTEN wild-type prostate cancer treated with PI3K/mTOR inhibitors.

Main Methods:

  • Utilized PTEN wild-type and mutant prostate cancer cell lines (CWR22/22RV1 and LNCaP).
  • Treated cells with the dual PI3K/mTOR inhibitor DS-7423 alone and in combination with HER2 or mGluR1 inhibitors.
  • Assessed protein expression (PSMA, mGluR1, HER2, androgen receptor, HER3) and cell survival.
  • Conducted xenograft studies to evaluate tumor growth inhibition.

Main Results:

  • PTEN wild-type cells upregulate PSMA, mGluR1, and HER2 upon DS-7423 treatment, forming a resistance feedback loop.
  • PTEN-mutant cells upregulate androgen receptor and HER3.
  • Combination therapy (DS-7423 with HER2 or mGluR1 inhibitors) significantly decreased cell survival and tumor growth in vivo.

Conclusions:

  • A positive feedback loop involving PSMA, mGluR1, and HER2 contributes to DS-7423 resistance in PTEN wild-type prostate cancer.
  • Combining PI3K/mTOR blockade with HER2 or mGluR1 inhibition presents a promising therapeutic approach for PTEN wild-type, PI3K/AKT-mutant prostate cancer.
  • This study identifies a novel therapeutic avenue for a subset of prostate cancer patients with limited treatment options.

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