Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer
Abstract The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eve...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2024-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-07272-7 |
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| author | Josephina Sampson Hyun-min Ju Nan Zhang Sharon Yeoh Jene Choi Richard Bayliss |
| author_facet | Josephina Sampson Hyun-min Ju Nan Zhang Sharon Yeoh Jene Choi Richard Bayliss |
| author_sort | Josephina Sampson |
| collection | DOAJ |
| description | Abstract The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR). Using phosphopeptide chip array and upstream kinase prediction analysis, we identified a group of phosphorylated tyrosine peptides including ERBB and AKT proteins that are upregulated upon ALK-TKI treatment in EML4-ALK-positive NSCLC cell lines. Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling pathways, and enhances apoptosis in EML4-ALK + NSCLC cancer cells. Heregulin, an ERBB3 ligand, differentially modulates the sensitivity of EML4-ALK cell lines to ALK inhibitors. We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC. |
| format | Article |
| id | doaj-art-e85e8191064849ecba5404cda5af27e6 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-e85e8191064849ecba5404cda5af27e62025-08-20T01:57:13ZengNature Publishing GroupCell Death and Disease2041-48892024-12-01151212110.1038/s41419-024-07272-7Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancerJosephina Sampson0Hyun-min Ju1Nan Zhang2Sharon Yeoh3Jene Choi4Richard Bayliss5Astbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of LeedsDepartment of Pathology, Asan Medical Center, University of Ulsan College of MedicineAstbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of LeedsAstbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of LeedsDepartment of Pathology, Asan Medical Center, University of Ulsan College of MedicineAstbury Centre for Structural Molecular Biology and School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of LeedsAbstract The fusion event between EML4 and ALK drives a significant oncogenic activity in 5% of non-small cell lung cancer (NSCLC). Even though potent ALK-tyrosine kinase inhibitors (ALK-TKIs) are successfully used for the treatment of EML4-ALK-positive NSCLC patients, a subset of those patients eventually acquire resistance during their therapy. Here, we investigate the kinase responses in EML4-ALK V1 and V3-harbouring NSCLC cancer cells after acute inhibition with ALK TKI, lorlatinib (LOR). Using phosphopeptide chip array and upstream kinase prediction analysis, we identified a group of phosphorylated tyrosine peptides including ERBB and AKT proteins that are upregulated upon ALK-TKI treatment in EML4-ALK-positive NSCLC cell lines. Dual inhibition of ALK and ERBB receptors or AKT disrupts RAS/MAPK and AKT/PI3K signalling pathways, and enhances apoptosis in EML4-ALK + NSCLC cancer cells. Heregulin, an ERBB3 ligand, differentially modulates the sensitivity of EML4-ALK cell lines to ALK inhibitors. We found that EML4-ALK cells made resistant to LOR are sensitive to inhibition of ERBB and AKT. These findings emphasize the important roles of AKT and ERBB3 to regulate signalling after acute LOR treatment, identifying them as potential targets that may be beneficial to prevent adaptive resistance to EML4-ALK-targeted therapies in NSCLC.https://doi.org/10.1038/s41419-024-07272-7 |
| spellingShingle | Josephina Sampson Hyun-min Ju Nan Zhang Sharon Yeoh Jene Choi Richard Bayliss Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer Cell Death and Disease |
| title | Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer |
| title_full | Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer |
| title_fullStr | Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer |
| title_full_unstemmed | Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer |
| title_short | Targeting ERBB3 and AKT to overcome adaptive resistance in EML4-ALK-driven non-small cell lung cancer |
| title_sort | targeting erbb3 and akt to overcome adaptive resistance in eml4 alk driven non small cell lung cancer |
| url | https://doi.org/10.1038/s41419-024-07272-7 |
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