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Targeting HTR2B suppresses nonfunctioning pituitary adenoma growth and sensitizes cabergoline treatment via

Shaojian Lin1, Liangbo Wang2, Changxi Han1

  • 1Department of Neurosurgery, Center of Pituitary Tumor, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Neuro-Oncology
|July 11, 2024
PubMed
Abstract

Insights

Targeting HTR2B shows promise for treating nonfunctioning pituitary adenomas (NFPAs). Inhibiting HTR2B enhances cabergoline (CAB) efficacy, suggesting a dual therapy approach for NFPAs with high HTR2B expression.

Area of Science:

  • Endocrinology
  • Oncology
  • Molecular Biology

Background:

  • Nonfunctioning pituitary adenomas (NFPAs) present management challenges due to limited effective drug therapies.
  • The efficacy of cabergoline (CAB) in treating NFPAs remains debated, necessitating exploration of alternative therapeutic targets.
  • The serotonin receptor 2B (HTR2B) role in NFPAs and its potential as a therapeutic target require further investigation.

Purpose of the Study:

  • To investigate the expression and functional significance of HTR2B in nonfunctioning pituitary adenomas (NFPAs).
  • To evaluate the therapeutic potential of modulating HTR2B activity, alone and in combination with cabergoline (CAB), for NFPA treatment.
  • To elucidate the molecular mechanisms underlying HTR2B-mediated signaling pathways in pituitary tumor cells.

Main Methods:

  • Bulk RNA-sequencing data analysis to quantify HTR2B expression in NFPA samples.
  • In vitro and in vivo experimental models to assess the impact of HTR2B modulation on tumor growth and cell cycle.
  • Pharmacological inhibition and molecular assays to delineate the HTR2B signaling cascade involving Gαq/PLC/PKC and STAT3 pathways.

Main Results:

  • Elevated HTR2B expression in NFPAs correlates with increased tumor survival.
  • Inhibition of HTR2B suppressed tumor growth by modulating the G2M cell cycle and blocking STAT3 phosphorylation via the Gαq/PLC/PKC pathway.
  • Cabergoline (CAB) activates STAT3 through HTR2B, potentially limiting its therapeutic effect. Combination therapy with an HTR2B antagonist (PRX-08066) and CAB significantly inhibited proliferation in preclinical models and patient-derived samples.
  • A molecular signature of upregulated HTR2B/PKC-γ and downregulated BTG2/GADD45A may predict response to dual therapy.

Conclusions:

  • HTR2B represents a promising therapeutic target for nonfunctioning pituitary adenomas (NFPAs).
  • Inhibition of HTR2B can enhance the efficacy of cabergoline (CAB) therapy.
  • A combination therapy targeting HTR2B and utilizing CAB may offer a beneficial treatment strategy for NFPA patients with high HTR2B expression.
Keywords:
Gαq/PLC/PKC-γHTR2BSTAT3cabergolinepituitary adenomas

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