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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
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Differential modulation of PI3K/Akt/mTOR activity by EGFR inhibitors: A rationale for co-targeting EGFR and PI3K in

Jipei Liao1, Zejia Yang1, Shirin Azarbarzin1

  • 1University of Maryland Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, USA.

Head & Neck
|March 2, 2024
PubMed
Abstract

Insights

Combining EGFR and PI3K inhibitors offers a new strategy for treating cisplatin-resistant head and neck squamous cell carcinoma (HNSCC). This combination therapy effectively suppresses tumor cell proliferation and induces apoptosis in resistant HNSCC models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cisplatin resistance is a major challenge in treating head and neck squamous cell carcinoma (HNSCC).
  • Epidermal Growth Factor Receptor (EGFR) inhibitors are used in HNSCC treatment, but resistance can develop.
  • The PI3K/Akt/mTOR pathway plays a critical role in cell survival and proliferation, and is often dysregulated in cancer.

Purpose of the Study:

  • To investigate the effects of EGFR inhibitors on the PI3K/Akt/mTOR pathway in cisplatin-resistant HNSCC.
  • To determine the efficacy of combining EGFR inhibitors with PI3K inhibitors against cisplatin-resistant HNSCC.

Main Methods:

  • Cisplatin-resistant HNSCC cell lines were treated with FDA-approved EGFR inhibitors (Gefitinib, Erlotinib) alone or with the pan-PI3K inhibitor BKM120.
  • Western blot analysis was used to assess protein phosphorylation and levels.
  • Cell proliferation was measured by MTS assay, and apoptosis was analyzed by flow cytometry.

Main Results:

  • Cisplatin-resistant HNSCC cells exhibited resistance to EGFR inhibitors alone.
  • Combination therapy with EGFR inhibitors and BKM120 significantly enhanced the inhibition of cell proliferation and induced apoptosis.
  • Combined treatment completely blocked the phosphorylation of EGFR, Akt, and S6K, a downstream target of mTOR.

Conclusions:

  • EGFR inhibitors alone are not effective against cisplatin-resistant HNSCC.
  • Combining EGFR inhibitors with PI3K inhibitors presents a promising therapeutic strategy for overcoming cisplatin resistance in HNSCC.
  • Targeting both EGFR and PI3K pathways offers a rationale for treating resistant HNSCC.
Keywords:
EGFREGFR inhibitorHNSCCPI3KPI3K inhibitorscisplatin resistancetargeted therapy

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