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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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FBXL2 counteracts Grp94 to destabilize EGFR and inhibit EGFR-driven NSCLC growth

Mengmeng Niu1, Jing Xu1, Yang Liu1

  • 1Center of Growth, Metabolism, and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.

Nature Communications
|October 12, 2021
PubMed

Insights

FBXL2 targets epidermal growth factor receptor (EGFR) for degradation, suppressing non-small cell lung cancer (NSCLC). Nebivolol upregulates FBXL2, offering a new strategy for TKI-resistant NSCLC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Abnormal epidermal growth factor receptor (EGFR) activation drives non-small cell lung cancer (NSCLC).
  • EGFR mutations confer resistance to tyrosine-kinase inhibitors (TKIs), a significant challenge in NSCLC treatment.

Purpose of the Study:

  • To investigate the role of F-box protein FBXL2 in regulating EGFR stability and its implications in NSCLC.
  • To explore glucose-regulated protein 94 (Grp94) as a modulator of EGFR degradation.
  • To identify therapeutic strategies targeting the FBXL2-Grp94-EGFR axis for TKI-resistant NSCLC.

Main Methods:

  • Investigated FBXL2's interaction with EGFR and its role in proteasomal degradation.
  • Assessed the impact of FBXL2 expression levels on NSCLC patient outcomes.
  • Examined the protective mechanism of Grp94 against FBXL2-mediated EGFR degradation.
  • Evaluated the efficacy of nebivolol in upregulating FBXL2 and inhibiting NSCLC growth.
  • Tested combination therapies involving nebivolol, osimertinib, and a Grp94 inhibitor.

Main Results:

  • FBXL2 targets both wild-type and TKI-resistant EGFR mutants for proteasomal degradation, suppressing NSCLC growth.
  • Reduced FBXL2 expression correlates with poor clinical outcomes in NSCLC patients.
  • Grp94 protects EGFR by preventing FBXL2 binding.
  • Nebivolol upregulates FBXL2, inhibiting EGFR-driven NSCLC.
  • Nebivolol combined with osimertinib or a Grp94 inhibitor shows potent inhibition of osimertinib-resistant NSCLC.

Conclusions:

  • The FBXL2-Grp94-EGFR axis is crucial in NSCLC pathogenesis.
  • Targeting this axis to destabilize EGFR presents a potential therapeutic strategy for TKI-resistant NSCLC.

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