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Targeting the IGF1R/PI3K/AKT Pathway Sensitizes Ewing Sarcoma to BET Bromodomain Inhibitors

Sudan N Loganathan1,2,3, Nan Tang4, Albert E Holler1

  • 1Department of Neurological Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.

Molecular Cancer Therapeutics
|March 31, 2019
PubMed

Insights

Combining IGF1R inhibitors with BET inhibitors overcomes resistance in Ewing sarcoma. This combination therapy shows potent apoptosis and durable tumor response, offering a new strategy for advanced disease.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Bromodomain and extra-terminal domain (BET) inhibitors show moderate efficacy in Ewing sarcoma.
  • Mechanisms of intrinsic resistance to BET inhibitors require elucidation.
  • Developing combination therapies is crucial for improving treatment outcomes.

Purpose of the Study:

  • Identify resistance mechanisms to BET inhibitors in Ewing sarcoma.
  • Develop effective combination treatments by targeting resistance pathways.
  • Evaluate the synergistic effects of combining BET inhibitors with other agents.

Main Methods:

  • Utilized Ewing sarcoma cell lines and patient-derived xenograft (PDX) models.
  • Assessed the impact of Insulin-like Growth Factor 1 Receptor (IGF1R) inhibitors and mechanistic Target of Rapamycin (mTOR) inhibitors in combination with BET inhibitors.
  • Investigated the role of the PI3K/AKT pathway in mediating resistance.

Main Results:

  • IGF1R inhibitors synergize with BET inhibitors, inducing potent apoptosis in Ewing sarcoma.
  • Constitutively activated AKT confers resistance to BET inhibitors, highlighting the PI3K/AKT pathway's role.
  • Combination therapy of BET and IGF1R inhibitors demonstrated potent and durable responses in xenograft tumors.
  • Ewing sarcoma cells resistant to IGF1R inhibitors still responded synergistically to BET and mTOR inhibitors.

Conclusions:

  • IGF1R and the PI3K/AKT/mTOR pathway mediate intrinsic resistance to BET inhibitors in Ewing sarcoma.
  • Combination of BET inhibitors with agents targeting the IGF1R pathway is a promising strategy for advanced Ewing sarcoma.
  • These findings provide a proof-of-concept for novel combination therapies in Ewing sarcoma treatment.

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