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s41419-025-07513-3.pdf (2.51 MB)

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2025-03-20

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cc-by (c) Martín, Fernando et al., 2025
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/221540

Novel selective strategies targeting the BCL-2 family to enhance clinical efficacy in ALK-rearranged non-small cell lung cancer

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ALK (anaplastic lymphoma kinase) rearrangements represent the third most predominant driver oncogene in non-small cell lung cancer (NSCLC). Although ALK inhibitors are the tyrosine kinase inhibitors (TKIs) with the longest survival rates in lung cancer, the complex systemic clinical evaluation and the apoptotic cell death evasion of drug-tolerant persister (DTP) cancer cells may limit their therapeutic response. We found that dynamic BH3 profiling (DBP) presents an excellent predictive capacity to ALK-TKIs, that would facilitate their use in a clinical setting and complementing the readout of standard diagnostic assays. In addition, we revealed novel acute adaptive mechanisms in response to ALK inhibitors in cell lines and patient-derived tumor cells. Consistently, all our cell models confirmed a rapid downregulation of the sensitizer protein NOXA, leading to dependence on the anti-apoptotic protein MCL-1 after treatment with ALK-TKIs. In some cases, the anti-apoptotic protein BCL-xL may contribute equally to this anti-apoptotic response. Importantly, these acute dependencies could be prevented with BH3 mimetics in vitro and in vivo, blocking tumor adaptation to treatment. Finally, we also demonstrated how dual reactivation of PI3K/AKT and MAPK signaling pathways can impair lorlatinib response, which could be overcome with specific inhibitors of both signaling pathways. In conclusion, our findings propose several therapeutic combinations that should be explored in future clinical trials to enhance ALK inhibitors efficacy and improve the clinical response in a broad NSCLC patient population.

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Matèries

Càncer de pulmó, Oncogens, Tractament adjuvant del càncer

Matèries (anglès)

Lung cancer, Oncogenes, Adjuvant treatment of cancer

Citació

Col·leccions

Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (Enginyeria Electrònica i Biomèdica)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)
Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))
Articles publicats en revistes (Medicina)

Citació

MARTÍN, Fernando, ALCON, Clara, MARÍN, Elba, MORALES SÁNCHEZ, Paula, MANZANO MUÑOZ, Albert, DIAZ, Sherley, GARCÍA LÓPEZ, Mireia, SAMITIER I MARTÍ, Josep, LU, Albert, VILLANUEVA GARATACHEA, Alberto, REGUART, Noemí, TEIXIDO FEBRERO, Cristina, MONTERO BORONAT, Joan. Novel selective strategies targeting the BCL-2 family to enhance clinical efficacy in ALK-rearranged non-small cell lung cancer. _Cell Death and Disease_. 2025. Vol. 16. [consulta: 25 de novembre de 2025]. ISSN: 2041-4889. [Disponible a: https://hdl.handle.net/2445/221540]

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