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Suppression of Tumor Cell Lactate-generating Signaling Pathways Eradicates Murine PTEN/p53-deficient

Kiranj Chaudagar1, Hanna M Hieromnimon1, Anne Kelley1

  • 1Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, Illinois.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|September 18, 2023
PubMed
Abstract

Insights

Targeting PI3K pathway resistance in aggressive prostate cancer with combined inhibitors suppressed lactate and improved tumor control. Further combination therapy achieved complete, durable tumor regression by blocking Wnt/β-catenin signaling.

Area of Science:

  • Oncology
  • Immunometabolism
  • Prostate Cancer Research

Background:

  • Loss of Phosphatase and tensin homolog (PTEN) function and PI3K pathway hyperactivation are linked to poor therapeutic outcomes and resistance to immune checkpoint inhibitors in various cancers.
  • Aggressive-variant prostate cancer (AVPC) with PTEN/p53 deficiency exhibits unique immunometabolic characteristics.
  • Previous studies showed partial tumor control with PI3K inhibitor (PI3Ki) and PD-1 antibody by disrupting lactate crosstalk between cancer cells and tumor-associated macrophages (TAMs).

Purpose of the Study:

  • To investigate immunometabolic mechanisms driving resistance to PI3K inhibitors (PI3Ki) in aggressive-variant prostate cancer (AVPC).
  • To achieve durable tumor control in PTEN/p53-deficient AVPC models.
  • To explore combination therapies targeting resistance pathways.

Main Methods:

  • Utilized genetically engineered mouse (GEM) models of PTEN/p53-deficient AVPC.
  • Administered PI3Ki (copanlisib), MEK inhibitor (trametinib), and Porcupine inhibitor (LGK'974) alone and in combination.
  • Monitored tumor kinetics using MRI and performed immune/proteomic profiling and ex vivo coculture studies.

Main Results:

  • Combination of PI3Ki and MEK inhibitor (trametinib) increased overall response rate to 80% by suppressing lactate and histone lactylation (H3K18lac) in TAMs, compared to PI3Ki monotherapy (37.5%).
  • Resistant tumors (20%) exhibited feedback activation of Wnt/β-catenin signaling, restoring lactate secretion and H3K18lac.
  • Triple combination therapy (PI3Ki/MEKi/Porcupine inhibitor) achieved durable tumor control in 100% of mice by suppressing H3K18lac and fully activating TAMs.

Conclusions:

  • Abrogating lactate-mediated crosstalk between cancer cells and TAMs leads to durable, androgen deprivation therapy-independent tumor control in PTEN/p53-deficient AVPC.
  • Targeting Wnt/β-catenin signaling is crucial for overcoming PI3Ki/MEKi resistance.
  • The findings warrant further investigation in clinical trials for AVPC treatment.

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