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

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

  • Cell Death Dis. 2025 Mar 20;16(1):194. doi: 10.1038/s41419-025-07513-3.
Fernando Martín 1 2 3,  Clara Alcon 3,  Elba Marín 4 5 6,  Paula Morales-Sánchez 3,  Albert Manzano-Muñoz 1 3,  Sherley Díaz 7,  Mireia García 7,  Josep Samitier 1 2 8,  Albert Lu 3,  Alberto Villanueva 9,  Noemí Reguart 4 5 6 10,  Cristina Teixido 5 6 7 10,  Joan Montero 11 12
Affiliations

Affiliations

  • 1 Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
  • 2 Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain.
  • 3 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
  • 4 Division of Medical Oncology, Hospital Clínic, Barcelona, Spain.
  • 5 Translational Genomics and Targeted Therapies in Solid Tumors, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
  • 6 Unitat funcional de Tumors Toràcics, Hospital Clínic, Barcelona, Spain.
  • 7 Department of Pathology and CORE Molecular Biology Laboratory, Hospital Clínic, Barcelona, Spain.
  • 8 Department of Electronics and Biomedical Engineering, Faculty of Physics, University of Barcelona, Barcelona, Spain.
  • 9 Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Spain.
  • 10 Department of Medicine, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain.
  • 11 Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain. jmontero@ub.edu.
  • 12 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain. jmontero@ub.edu.
PMID: 40113795 DOI: 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.

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