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Updated: Jan 30, 2026

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
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PI3K oncogenic mutations mediate resistance to afatinib in HER2/neu overexpressing gynecological cancers

Elena Bonazzoli1, Emiliano Cocco2, Salvatore Lopez3

  • 1Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.

Gynecologic Oncology
|January 12, 2019
PubMed
Abstract

Insights

Oncogenic PIK3CA mutations confer resistance to afatinib in endometrial and ovarian cancers. Combining afatinib with PIK3CA, AKT, or mTOR inhibitors may improve treatment efficacy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Aberrant HER2/neu and PIK3CA expression is common in high-grade-serous-endometrial (USC) and ovarian cancers (HGSOC).
  • PIK3CA mutations may confer resistance to targeted therapies like afatinib, but this is not well-studied.

Purpose of the Study:

  • To investigate the role of oncogenic PIK3CA mutations as a mechanism of resistance to afatinib in HER2/neu-overexpressing HGSOC and USC.
  • To evaluate the impact of specific PIK3CA mutations (H1047R/E545K) on afatinib efficacy in vitro and in vivo.

Main Methods:

  • Utilized whole-exome-sequenced cell lines and xenografts from HGSOC/USC with mutated or wild-type PIK3CA/PIK3R1.
  • Transfected USC cell lines with oncogenic PIK3CA mutations and assessed afatinib's effect on the HER2/PI3K/AKT/mTOR pathway via immunoblotting.

Main Results:

  • PIK3CA-mutated cell lines showed significantly lower sensitivity to afatinib (higher IC50) compared to wild-type lines (p=0.004).
  • Xenografts with PIK3CA mutations exhibited more rapid tumor growth under afatinib treatment versus wild-type controls (p=0.041 and p=0.001).
  • Afatinib reduced HER2 phosphorylation but led to a compensatory increase in phosphorylated AKT in PIK3CA-mutated cells.

Conclusions:

  • Oncogenic PIK3CA mutations are a significant mechanism of resistance to afatinib in USC and HGSOC.
  • Combination therapies involving afatinib with PIK3CA, AKT, or mTOR inhibitors may be required for effective PI3K/AKT/mTOR pathway blockade.
Keywords:
AfatinibGynecological cancerHER2/neu overexpressionMechanism of resistancePI3K mutation

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