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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
Please use this identifier to cite or link to this item: 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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https://doi.org/10.1038/s41419-025-07513-3

Abstract

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.

Subject

Càncer de pulmó, Oncogens, Tractament adjuvant del càncer

Subject (English)

Lung cancer, Oncogenes, Adjuvant treatment of cancer

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

Citation

MARTÍN, Fernando, et al. 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. ISSN 2041-4889. [consulted: 15 of August of 2026]. Available at: https://hdl.handle.net/2445/221540

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