Combined Inhibitions of Glycolysis and AKT/autophagy Can Overcome Resistance to EGFR-targeted Therapy of Lung Cancer

Abstract

Efficacy of EGFR-targeted tyrosine kinase inhibitors (TKIs), such as erlotinib, to treat human non-small cell lung cancers (NSCLCs) with activating mutations in EGFR is not persistent due to drug resistance. Reprogramming in energy (especially glucose) metabolism plays an important role in development and progression of acquired resistance in cancer cells. We hypothesize that glucose metabolism in EGFR-TKI sensitive HCC827 cells and erlotinib-resistant sub-line of HCC827 (which we name it as erlotinib-resistant 6, ER6 cells in this study) is different and targeting glucose metabolism might be a treatment strategy for erlotinib-resistant NSCLCs. In this study, we found increased glucose uptakes, significant increase in glycolysis rate and overexpression of glucose transporter 1 in ER6 cells compared to its parental cells HCC827. We also found AKT and autophagy of ER6 cells were more activated than HCC827 cells after glucose starvation. Combining glucose deprivation and AKT or autophagy inhibitor could synergize and overcome the acquired resistance against EGFR-targeted therapy for NSCLCs. Our data suggest that the combinations of inhibitors of AKT or autophagy together with glucose deprivation could be novel treatment strategies for NSCLC with acquired resistance to targeted therapy.

Multiple roles and regulatory mechanisms of the transcription factor GATA6 in human cancers

“…This method not only has the advantages of non‐invasiveness, accuracy, and low price, but also complements chest X‐ray and computed tomography in diagnosing LC . Autophagy has been reported to promote cancer development and chemoresistance and is thought to be associated with TKI resistance . Upregulation of GATA6 gene expression can enhance autophagy levels and promote TKI resistance in NSCLC …”

“…36 Autophagy has been reported to promote cancer development and chemoresistance and is thought to be associated with TKI resistance. 37,38 Upregulation of GATA6 gene expression can enhance autophagy levels and promote TKI resistance in NSCLC. 39 The level of the transcription factor GATA6 in vivo is closely related to the development of LC.…”

Autophagy determines osimertinib resistance through regulation of stem cell-like properties in EGFR-mutant lung cancer

“…On the other hand, reports demonstrated that gefitinib and erlotinib induced pro-cell survival autophagy in both sensitive and resistant cancer cells (Han et al, 2011; Sugita et al, 2015; Zou et al, 2013). Combining glucose deprivation and autophagy inhibitor could synergize and overcome the acquired resistance against erlotinib (Ye et al, 2017). Taken together, the role of autophagy in resistance to 1 st and 2 nd generation EGFR-TKI is contradictory.…”

Metformin‐sensitized NSCLC cells to osimertinib via AMPK‐dependent autophagy inhibition

“…The mechanism for resistance to osimertinib is not completely clear. Previous study showed that osimertinib induced an accompanied autophagy which contributed to EGFR‐TKI resistance . Thus, autophagy inhibition might be potential therapeutic way to sensitize osimertinib and delay the emergency of resistance.…”