A Study of Alternative TrkA Splicing Identifies TrkAIII as a Novel Potentially Targetable Participant in PitNET...

Area of Science:

• Endocrinology
• Molecular Biology
• Oncology

Background:

• Pituitary neuroendocrine tumors (PitNETs) have an aggressive subset requiring new therapeutic targets.
• Alternative splicing is an oncogenic pathway in PitNETs.
• The neurotrophin receptor TrkA, with oncogenic TrkAIII splicing, is expressed in PitNETs.

Purpose of the Study:

• To investigate the role of TrkAIII splicing in PitNET pathogenesis and progression.
• To determine if TrkAIII splicing represents a potential oncogenic participant in PitNETs.

Main Methods:

• Assessed TrkAIII splicing via RT-PCR in 53 PitNETs.
• Evaluated TrkA isoform expression and activation using confocal immunofluorescence.
• Compared TrkAIII splicing with expression of HIF1α, HIF2α, SF3B1, SRSF2, U2AF1, JCPyV large T antigen, Xbp1 splicing, and SF3B1 mutations.

Main Results:

• TrkAIII splicing was detected in all invasive and most non-invasive PitNETs, significantly elevated in invasive cases.
• TrkAIII splicing was higher in invasive PIT1 PitNETs and in SF1 and TPIT lineages.
• TrkAIII activation was observed in PitNETs with TrkAIII mRNA; invasive Pit1 PitNETs showed increased HIF2α expression.

Conclusions:

• TrkAIII splicing is prevalent in PitNETs, especially invasive subtypes, and can lead to TrkAIII activation.
• Hypoxia may be involved in TrkAIII splicing in PitNETs.
• TrkAIII represents a potential novel therapeutic target for refractory PitNETs.