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| Natura: | Artículo científico |
| Lingua: | en |
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Anticancer research
2026
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| Accesso online: | https://pubmed.ncbi.nlm.nih.gov/41895783/ |
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| _version_ | 1868266067052199936 |
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| author | Dela Cruz, Ma Carmela Yao, Xin Nealy, Alajah Bailey, James Nalls, Micah Medina, Paul Mark Chen, Renwei Biliran, Hector |
| author_facet | Dela Cruz, Ma Carmela Yao, Xin Nealy, Alajah Bailey, James Nalls, Micah Medina, Paul Mark Chen, Renwei Biliran, Hector Dela Cruz, Ma Carmela Yao, Xin Nealy, Alajah Bailey, James Nalls, Micah Medina, Paul Mark Chen, Renwei Biliran, Hector |
| collection | PubMed - marine biology |
| contents | BIT1 as an Effector of EGFR-TKI-induced Apoptosis TLE1 Inhibition in Lung Adenocarcinoma Cells. Dela Cruz, Ma Carmela Yao, Xin Nealy, Alajah Bailey, James Nalls, Micah Medina, Paul Mark Chen, Renwei Biliran, Hector Humans Apoptosis ErbB Receptors Lung Neoplasms Adenocarcinoma of Lung Protein Kinase Inhibitors Drug Resistance, Neoplasm Co-Repressor Proteins Cell Line, Tumor Mitochondrial Proteins Gene Expression Regulation, Neoplastic Carboxylic Ester Hydrolases Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) remains a substantial clinical obstacle in treating lung adenocarcinoma (LUAD). Identifying pro-survival pathways that allow tumor cells to evade TKI-induced apoptosis is critical for overcoming this resistance. The transcriptional repressor transducin-like enhancer of split 1 (TLE1) was previously identified as a crucial oncogenic factor that promotes survival in resistant cells. This study investigates the mitochondrial protein Bcl-2 inhibitor of transcription 1 (Bit1) as a key pro-apoptotic signal that overrides the TLE1-mediated survival program. EGFR-TKI sensitive, resistant, and drug-tolerant persister LUAD models were utilized. Bit1 release and TLE1 translocation were assessed subcellular fractionation. Cell fate following genetic manipulation was determined through viability and apoptosis assays, while RNA-sequencing identified TLE1-regulated transcriptional changes. In sensitive EGFR-mutant non-small cell lung cancer (NSCLC) cells, TKI treatment triggers the rapid cytosolic release of the mitochondrial outer membrane permeabilization (MOMP)-tethered protein Bit1. This early mobilization precedes cytochrome C release and occurs independently of full MOMP, identifying the Bit1 pathway as a novel, early-response death signal in lung cancer. While Bit1 downregulation attenuated EGFR-TKI-induced apoptosis in EGFR-mutant lung adenocarcinoma cells, ectopic mitochondrial Bit1 expression restored TKI sensitivity in resistant cells. Mechanistically, TKI exposure triggered cytosolic Bit1-AES complex formation, resulting in the nuclear exclusion and sequestration of TLE1. This axis is also pivotal in adaptive resistance; TLE1 was upregulated in drug-tolerant persister (DTP) cells and required for their survival, while Bit1 activation attenuated DTP formation. Transcriptomic analysis revealed that TLE1 coordinates a resistance program enriched for EMT and Notch signaling. The Bit1/TLE1 axis is a pivotal regulatory switch dictating apoptotic outcomes following EGFR-TKI treatment. This mechanism identifies a therapeutic vulnerability, suggesting that pharmacological Bit1 pathway activation could be an effective strategy to overcome acquired resistance in LUAD. |
| format | Artículo científico |
| id | pubmed_41895783 |
| institution | PubMed |
| language | en |
| publishDate | 2026 |
| publisher | Anticancer research |
| record_format | pubmed |
| spellingShingle | BIT1 as an Effector of EGFR-TKI-induced Apoptosis TLE1 Inhibition in Lung Adenocarcinoma Cells. Dela Cruz, Ma Carmela Yao, Xin Nealy, Alajah Bailey, James Nalls, Micah Medina, Paul Mark Chen, Renwei Biliran, Hector Humans Apoptosis ErbB Receptors Lung Neoplasms Adenocarcinoma of Lung Protein Kinase Inhibitors Drug Resistance, Neoplasm Co-Repressor Proteins Cell Line, Tumor Mitochondrial Proteins Gene Expression Regulation, Neoplastic Carboxylic Ester Hydrolases BIT1 as an Effector of EGFR-TKI-induced Apoptosis TLE1 Inhibition in Lung Adenocarcinoma Cells. Dela Cruz, Ma Carmela Yao, Xin Nealy, Alajah Bailey, James Nalls, Micah Medina, Paul Mark Chen, Renwei Biliran, Hector Humans Apoptosis ErbB Receptors Lung Neoplasms Adenocarcinoma of Lung Protein Kinase Inhibitors Drug Resistance, Neoplasm Co-Repressor Proteins Cell Line, Tumor Mitochondrial Proteins Gene Expression Regulation, Neoplastic Carboxylic Ester Hydrolases Acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) remains a substantial clinical obstacle in treating lung adenocarcinoma (LUAD). Identifying pro-survival pathways that allow tumor cells to evade TKI-induced apoptosis is critical for overcoming this resistance. The transcriptional repressor transducin-like enhancer of split 1 (TLE1) was previously identified as a crucial oncogenic factor that promotes survival in resistant cells. This study investigates the mitochondrial protein Bcl-2 inhibitor of transcription 1 (Bit1) as a key pro-apoptotic signal that overrides the TLE1-mediated survival program. EGFR-TKI sensitive, resistant, and drug-tolerant persister LUAD models were utilized. Bit1 release and TLE1 translocation were assessed subcellular fractionation. Cell fate following genetic manipulation was determined through viability and apoptosis assays, while RNA-sequencing identified TLE1-regulated transcriptional changes. In sensitive EGFR-mutant non-small cell lung cancer (NSCLC) cells, TKI treatment triggers the rapid cytosolic release of the mitochondrial outer membrane permeabilization (MOMP)-tethered protein Bit1. This early mobilization precedes cytochrome C release and occurs independently of full MOMP, identifying the Bit1 pathway as a novel, early-response death signal in lung cancer. While Bit1 downregulation attenuated EGFR-TKI-induced apoptosis in EGFR-mutant lung adenocarcinoma cells, ectopic mitochondrial Bit1 expression restored TKI sensitivity in resistant cells. Mechanistically, TKI exposure triggered cytosolic Bit1-AES complex formation, resulting in the nuclear exclusion and sequestration of TLE1. This axis is also pivotal in adaptive resistance; TLE1 was upregulated in drug-tolerant persister (DTP) cells and required for their survival, while Bit1 activation attenuated DTP formation. Transcriptomic analysis revealed that TLE1 coordinates a resistance program enriched for EMT and Notch signaling. The Bit1/TLE1 axis is a pivotal regulatory switch dictating apoptotic outcomes following EGFR-TKI treatment. This mechanism identifies a therapeutic vulnerability, suggesting that pharmacological Bit1 pathway activation could be an effective strategy to overcome acquired resistance in LUAD. |
| title | BIT1 as an Effector of EGFR-TKI-induced Apoptosis TLE1 Inhibition in Lung Adenocarcinoma Cells. |
| topic | Humans Apoptosis ErbB Receptors Lung Neoplasms Adenocarcinoma of Lung Protein Kinase Inhibitors Drug Resistance, Neoplasm Co-Repressor Proteins Cell Line, Tumor Mitochondrial Proteins Gene Expression Regulation, Neoplastic Carboxylic Ester Hydrolases |
| url | https://pubmed.ncbi.nlm.nih.gov/41895783/ |