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The PIK3CA/AKT pathway drives therapy resistance in rhabdomyosarcoma

Qiqi Yang1,2,3,4, Yueyang Wang1,2,3, Luis A Corchete Sanchez2

  • 1Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, MA, USA.

Nature Communications
|December 10, 2025
PubMed

Insights

Olaparib and temozolomide (OT) therapy shows promise for rhabdomyosarcoma (RMS), but resistance emerges. Targeting the PIK3CA/AKT pathway with alpelisib can overcome this resistance, offering a new strategy for difficult-to-treat RMS.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Rhabdomyosarcoma (RMS) is a pediatric cancer with limited treatment options.
  • Olaparib and temozolomide (OT) combination therapy is under clinical investigation for RMS.
  • Acquired resistance to OT therapy is a significant challenge in various cancers, including RMS.

Purpose of the Study:

  • To investigate the mechanisms of OT resistance in RMS.
  • To identify potential therapeutic strategies to overcome OT resistance in RMS.
  • To evaluate the efficacy of combining OT with PIK3CA/AKT pathway inhibitors.

Main Methods:

  • Preclinical mouse xenograft models of RMS were utilized.
  • Transcriptomic analysis was performed on resistant and sensitive RMS tumors.
  • Pharmacological inhibition of the PIK3CA/AKT pathway was assessed using alpelisib.
  • Combination therapy studies involving OT and alpelisib were conducted.

Main Results:

  • OT effectively suppressed RMS tumor growth in preclinical models.
  • Over 50% of RMS tumors developed resistance to OT, characterized by transcriptomic alterations without recurrent genomic mutations.
  • Resistant RMS models frequently upregulated the PIK3CA/AKT pathway, leading to NRF2 activation and multidrug resistance ABC transporter expression.
  • Alpelisib re-sensitized resistant RMS cells to OT by inhibiting ABC transporter expression.
  • The combination of OT and alpelisib demonstrated efficacy against chemoresistant RMS and curbed tumor growth in vivo.

Conclusions:

  • A common resistance pathway involving PIK3CA/AKT activation and subsequent ABC transporter upregulation was identified in RMS.
  • PIK3CA/AKT pathway inhibition represents a promising preclinical strategy to overcome OT resistance in RMS.
  • Combination therapy with OT and alpelisib holds potential for treating therapy-resistant RMS.

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