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hnRNPM guides an alternative splicing program in response to inhibition of the PI3K/AKT/mTOR pathway in Ewing sarcoma

Ilaria Passacantilli1, Paola Frisone1, Elisa De Paola1,2

  • 1Laboratory of Cellular and Molecular Neurobiology, Fondazione Santa Lucia, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.

Nucleic Acids Research
|October 17, 2017
PubMed

Insights

Targeting the PI3K/AKT/mTOR pathway in Ewing sarcoma (ES) activates a splicing program regulated by hnRNPM. Inhibiting hnRNPM enhances treatment efficacy, suggesting a novel therapeutic strategy for this aggressive cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Ewing sarcoma (ES) is an aggressive bone and soft tissue tumor with limited treatment options.
  • The PI3K/AKT/mTOR signaling pathway is frequently dysregulated in ES, making it a therapeutic target.
  • Drug resistance and lack of effective chemotherapy are major challenges in ES treatment.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying therapeutic resistance in ES.
  • To identify novel therapeutic targets for ES by analyzing the effects of PI3K/AKT/mTOR inhibition.
  • To explore the role of alternative splicing in ES response to targeted therapy.

Main Methods:

  • Utilized splicing-sensitive arrays to analyze gene expression changes upon PI3K/AKT/mTOR pathway inhibition with BEZ235.
  • Performed bioinformatics analyses to identify key regulatory factors involved in splicing alterations.
  • Conducted hnRNPM knockdown experiments to assess its functional role in ES cells and therapeutic response.

Main Results:

  • Inhibition of the PI3K/AKT/mTOR pathway with BEZ235 induced a significant alternative splicing program in ES cells.
  • hnRNPM was identified as a crucial regulator of this splicing program, binding to introns near regulated exons.
  • hnRNPM knockdown sensitized ES cells to BEZ235, reduced tumor cell growth, and correlated with poor patient outcomes.

Conclusions:

  • An hnRNPM-dependent alternative splicing program is activated by PI3K/AKT/mTOR pathway inhibition in ES.
  • This splicing program contributes to therapeutic resistance and limits the efficacy of targeted inhibitors.
  • Combined inhibition of the PI3K/AKT/mTOR pathway and hnRNPM represents a promising novel therapeutic strategy for ES treatment.

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