PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs
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 clin...
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| Format: | Article |
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MDPI AG
2021-07-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/10/7/1679 |
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| author | Nadiia Lypova Susan M. Dougherty Lilibeth Lanceta Jason Chesney Yoannis Imbert-Fernandez |
| author_facet | Nadiia Lypova Susan M. Dougherty Lilibeth Lanceta Jason Chesney Yoannis Imbert-Fernandez |
| author_sort | Nadiia Lypova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T09:43:02Z |
| format | Article |
| id | doaj.art-4965fb7a8acf4f9baf9b6f4ce0194193 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T09:43:02Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-4965fb7a8acf4f9baf9b6f4ce01941932023-11-22T03:28:17ZengMDPI AGCells2073-44092021-07-01107167910.3390/cells10071679PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCsNadiia Lypova0Susan M. Dougherty1Lilibeth Lanceta2Jason Chesney3Yoannis Imbert-Fernandez4Department of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USADepartment of Medicine, School of Medicine, University of Louisville, Louisville, KY 40202, USATyrosine 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.https://www.mdpi.com/2073-4409/10/7/1679autophagy fluxlung cancerepidermal growth factor receptor (EGFR)6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3)cytoprotective autophagy |
| spellingShingle | Nadiia Lypova Susan M. Dougherty Lilibeth Lanceta Jason Chesney Yoannis Imbert-Fernandez PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs Cells autophagy flux lung cancer epidermal growth factor receptor (EGFR) 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) cytoprotective autophagy |
| title | PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs |
| title_full | PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs |
| title_fullStr | PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs |
| title_full_unstemmed | PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs |
| title_short | PFKFB3 Inhibition Impairs Erlotinib-Induced Autophagy in NSCLCs |
| title_sort | pfkfb3 inhibition impairs erlotinib induced autophagy in nsclcs |
| topic | autophagy flux lung cancer epidermal growth factor receptor (EGFR) 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) cytoprotective autophagy |
| url | https://www.mdpi.com/2073-4409/10/7/1679 |
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