Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer
Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-05-01
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| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/14/11/2613 |
| _version_ | 1797493968047439872 |
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| author | Celia Delahaye Sarah Figarol Anne Pradines Gilles Favre Julien Mazieres Olivier Calvayrac |
| author_facet | Celia Delahaye Sarah Figarol Anne Pradines Gilles Favre Julien Mazieres Olivier Calvayrac |
| author_sort | Celia Delahaye |
| collection | DOAJ |
| description | Lung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP. |
| first_indexed | 2024-03-10T01:27:35Z |
| format | Article |
| id | doaj.art-40d4fe6b50ae45f9a97bdc4fe36cbd31 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:27:35Z |
| publishDate | 2022-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-40d4fe6b50ae45f9a97bdc4fe36cbd312023-11-23T13:48:10ZengMDPI AGCancers2072-66942022-05-011411261310.3390/cancers14112613Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung CancerCelia Delahaye0Sarah Figarol1Anne Pradines2Gilles Favre3Julien Mazieres4Olivier Calvayrac5Cancer Research Centre of Toulouse, INSERM UMR1037, CNRS UMR5071, UPS, 31100 Toulouse, FranceCancer Research Centre of Toulouse, INSERM UMR1037, CNRS UMR5071, UPS, 31100 Toulouse, FranceCancer Research Centre of Toulouse, INSERM UMR1037, CNRS UMR5071, UPS, 31100 Toulouse, FranceCancer Research Centre of Toulouse, INSERM UMR1037, CNRS UMR5071, UPS, 31100 Toulouse, FranceCancer Research Centre of Toulouse, INSERM UMR1037, CNRS UMR5071, UPS, 31100 Toulouse, FranceCancer Research Centre of Toulouse, INSERM UMR1037, CNRS UMR5071, UPS, 31100 Toulouse, FranceLung cancer is the leading cause of cancer-related deaths among men and women worldwide. Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective therapies for advanced non-small-cell lung cancer (NSCLC) patients harbouring EGFR-activating mutations, but are not curative due to the inevitable emergence of resistances. Recent in vitro studies suggest that resistance to EGFR-TKI may arise from a small population of drug-tolerant persister cells (DTP) through non-genetic reprogramming, by entering a reversible slow-to-non-proliferative state, before developing genetically derived resistances. Deciphering the molecular mechanisms governing the dynamics of the drug-tolerant state is therefore a priority to provide sustainable therapeutic solutions for patients. An increasing number of molecular mechanisms underlying DTP survival are being described, such as chromatin and epigenetic remodelling, the reactivation of anti-apoptotic/survival pathways, metabolic reprogramming, and interactions with their micro-environment. Here, we review and discuss the existing proposed mechanisms involved in the DTP state. We describe their biological features, molecular mechanisms of tolerance, and the therapeutic strategies that are tested to target the DTP.https://www.mdpi.com/2072-6694/14/11/2613drug-tolerant persisterslung cancertargeted therapiesEGFR-TKI |
| spellingShingle | Celia Delahaye Sarah Figarol Anne Pradines Gilles Favre Julien Mazieres Olivier Calvayrac Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer Cancers drug-tolerant persisters lung cancer targeted therapies EGFR-TKI |
| title | Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer |
| title_full | Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer |
| title_fullStr | Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer |
| title_full_unstemmed | Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer |
| title_short | Early Steps of Resistance to Targeted Therapies in Non-Small-Cell Lung Cancer |
| title_sort | early steps of resistance to targeted therapies in non small cell lung cancer |
| topic | drug-tolerant persisters lung cancer targeted therapies EGFR-TKI |
| url | https://www.mdpi.com/2072-6694/14/11/2613 |
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