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PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs

Nadiia Lypova1, Susan M Dougherty1, Lilibeth Lanceta1

  • 1Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USA.

Cells
|August 7, 2021
PubMed

Insights

PFKFB3 inhibition overcomes erlotinib resistance in non-small cell lung cancer (NSCLC) by blocking autophagy. This study reveals a new link between PFKFB3 and EGFR signaling, improving erlotinib efficacy in NSCLC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Tyrosine kinase inhibitors (TKIs) targeting epidermal growth factor receptor (EGFR) have improved outcomes for non-small cell lung cancer (NSCLC).
  • Resistance to EGFR TKIs, like erlotinib, is a major clinical challenge, often involving enhanced prosurvival autophagy.
  • PFKFB3, a glycolysis regulator, has been previously linked to erlotinib resistance in NSCLC.

Purpose of the Study:

  • To investigate the role of PFKFB3 in mediating erlotinib-induced autophagy in NSCLC.
  • To determine if PFKFB3 inhibition can sensitize NSCLC cells to erlotinib by affecting autophagy.

Main Methods:

  • Pharmacological inhibition of PFKFB3 in NSCLC cell lines with varying EGFR mutation statuses.
  • Evaluation of erlotinib-induced autophagy flux following PFKFB3 inhibition.
  • Assessment of NSCLC cell response to combined PFKFB3 inhibition and erlotinib treatment.

Main Results:

  • PFKFB3 acts as a mediator of erlotinib-induced autophagy in NSCLC.
  • Inhibition of PFKFB3 significantly impairs autophagy flux in NSCLC cells.
  • PFKFB3 inhibition enhances the sensitivity of NSCLC cells to erlotinib.

Conclusions:

  • PFKFB3 is a key regulator of erlotinib-induced autophagy in NSCLC.
  • Targeting PFKFB3 represents a potential strategy to overcome erlotinib resistance.
  • A novel crosstalk between PFKFB3 and EGFR signaling pathways contributes to erlotinib sensitivity in NSCLC.
Keywords:
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3)autophagy fluxcytoprotective autophagyepidermal growth factor receptor (EGFR)lung cancer

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