PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs.
Nadiia LypovaSusan M DoughertyLilibeth LancetaJason ChesneyYoannis Imbert-FernandezPublished in: Cells (2021)
Tyrosine kinase inhibitors (TKIs) targeting the kinase domain of the epidermal growth factor receptor (EGFR), such as erlotinib, have dramatically improved clinical outcomes of patients with EGFR-driven non-small cell lung carcinomas (NSCLCs). However, intrinsic or acquired resistance remains a clinical barrier to the success of FDA-approved EGFR TKIs. Multiple mechanisms of resistance have been identified, including the activation of prosurvival autophagy. We have previously shown that the expression and activity of PFKFB3-a known driver of glycolysis-is associated with resistance to erlotinib and that PFKFB3 inhibition improves the response of NSCLC cells to erlotinib. This study focuses on investigating the role of PFKFB3 in regulating erlotinib-driven autophagy to escape resistance to erlotinib. We evaluated the consequence of pharmacological inhibition of PFKFB3 on erlotinib-driven autophagy in NSCLC cells with different mutation statuses. Here, we identify PFKFB3 as a mediator of erlotinib-induced autophagy in NSCLCs. We demonstrate that PFKFB3 inhibition sensitizes NCSLCs to erlotinib via impairing autophagy flux. In summary, our studies uncovered a novel crosstalk between PFKFB3 and EGFR that regulates erlotinib-induced autophagy, thus contributing to erlotinib sensitivity in NSCLCs.
Keyphrases
- epidermal growth factor receptor
- advanced non small cell lung cancer
- tyrosine kinase
- endoplasmic reticulum stress
- induced apoptosis
- cell death
- signaling pathway
- oxidative stress
- small cell lung cancer
- cell cycle arrest
- diabetic rats
- high glucose
- cell proliferation
- cancer therapy
- drug induced
- stem cells
- drug delivery
- drug administration