Carregant...
Fitxers
Tipus de document
TesiVersió
Versió publicadaData de publicació
Llicència de publicació
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/218517
Overcoming antiapoptotic adaptations to enhance non-small cell lung cancer treatment
Títol de la revista
Autors
Director/Tutor
ISSN de la revista
Títol del volum
Resum
[eng] The treatment of lung cancer has substantially progressed due to the development of targeted therapies against driver oncogenes. However, this type of cancer is still the leading cause of cancer-related mortality, requiring new strategies and treatments. In this context, genomic-based precision medicine has revolutionized the management of lung cancer, especially for non-small cell lung cancer (NSCLC). Nevertheless, these therapies are not always effective and often present limited clinical outcome. Thus, we believe that functional assays could be an excellent complement to genomic assays, as they can predict drug efficacy directly in patient-derived cancer cells. We initially evaluated the predictive capacity of the functional assay dynamic BH3 profiling (DBP) in a representative panel of NSCLC cell lines and targeted therapies. Our results confirmed that DBP was an excellent binary predictor in this subset of cells.
Precision medicine aims to assign the right therapy to the right patient and is becoming key for improving the survival of cancer patients. However, resistance is common through mutations and other genomic alterations, but other factors can also contribute to the potential relapse of patients, including the evasion of apoptotic cell death. In this study, we seek to better understand and overcome antiapoptotic adaptations to boost NSCLC treatment. We initially explored antiapoptotic adaptations in response to ALK inhibitors in cell lines and patient-derived tumor cells. All of these cell models showed a significant decrease in the expression of the sensitizer protein NOXA in response to ALK inhibitors, leading to an antiapoptotic MCL-1 dependence. In some instances, the antiapoptotic BCL-xL protein could also contribute to the evasion of apoptosis, requiring a case-by-case analysis to identify the antiapoptotic protein(s) involved in cell death protection. Importantly, these antiapoptotic adaptations could be overcome with BH3 mimetics or alternative approaches, enhancing the effectiveness of ALK inhibitors. Finally, we demonstrated that the reactivation of downstream PI3K/AKT and MAPK signaling pathways reduced the effectiveness of the third-generation ALK inhibitor lorlatinib, which could be overcome with specific inhibitors of these pathways.
The impairment of the mitochondrial apoptotic pathway is commonly associated with early adaptations to treatment. Nevertheless, the evasion of apoptosis can also contribute to other resistance mechanisms that appear after longer exposure to treatment, including cellular senescence. This cellular phenotype involves cell cycle arrest in response to stress signals such as chemotherapeutic agents, radiotherapy or cell cycle inhibitors. However, the impact of targeted therapies on senescence induction
2
is still unclear. In this study, we also demonstrated that the long-term treatment with the third-generation EGFR inhibitor osimertinib increased the expression of senescence markers. Furthermore, osimertinib-induced senescent cells acquired resistance to apoptosis through different molecular mechanisms that again converged in antiapoptotic MCL-1 and BCL-xL dependencies. Finally, the treatment with BH3 mimetics eliminated the majority of senescent cells, and we demonstrate their excellent senolytic efficacy in this context. In conclusion, we proposed novel therapeutic combinations to enhance the efficacy of targeted therapies in NSCLC, which could have a significant impact in the clinical setting in the future.
Descripció
Matèries (anglès)
Citació
Col·leccions
Citació
MARTÍN SILVA, Fernando. Overcoming antiapoptotic adaptations to enhance non-small cell lung cancer treatment. [consulta: 10 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/218517]