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Adaptive resistance to PI3Kα-selective inhibitor CYH33 is mediated by genomic and transcriptomic alterations in ESCC

Yu-Xiang Wang1, Xu Zhang1,2, Qing-Yang Ma3

  • 1Division of Anti-tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai, 201203, China.

Cell Death & Disease
|January 15, 2021
PubMed

Insights

Targeted therapies like PI3Kα inhibitors show promise for esophageal cancer but face resistance. This study identifies HRAS mutations as a key resistance mechanism and suggests combination therapies to overcome it.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Esophageal squamous cell carcinoma (ESCC) often exhibits PI3K pathway activation.
  • Phosphoinositide-3 kinase alpha-specific inhibitors (PI3Kαi) are a promising targeted therapy for ESCC.
  • Acquired resistance limits the long-term efficacy of targeted therapies, including PI3Kαi.

Purpose of the Study:

  • To investigate genomic adaptations leading to PI3Kαi resistance in ESCC.
  • To identify potential combination strategies to overcome PI3Kαi resistance in ESCC.

Main Methods:

  • Whole-genome sequencing of PI3Kαi-resistant ESCC cell lines.
  • Gene mutation and amplification analysis.
  • RNA sequencing to identify activated signaling pathways.
  • In vitro and in vivo drug sensitivity assays.

Main Results:

  • HRASG12S mutation was identified as a mechanism of acquired resistance to PI3Kαi CYH33 in ESCC cells.
  • Overexpression of HRASG12S conferred resistance, while its down-regulation restored sensitivity.
  • Elevated mTORC1, MAPK, and c-Myc signaling pathways were observed in resistant cells.
  • Combinations of CYH33 with MEK162, RAD001, or OTX015 demonstrated synergistic effects and overcame resistance.

Conclusions:

  • Genomic adaptation, particularly HRAS mutation, drives PI3Kαi resistance in ESCC.
  • Targeting downstream signaling pathways like MAPK and mTORC1 in combination with PI3Kαi can overcome resistance.
  • These findings provide a basis for developing effective combinatorial regimens for ESCC treatment.

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