New advances in the fight against the most common form of lung cancer. A study led by the University of Barcelona (UB) in collaboration with the Institute for Bioengineering of Catalonia (IBEC) reveals that the functional assay dynamic BH3 profiling (DBP) can predict whether specific treatments will be effective in non-small cell lung cancer patients. The technique of the study, published in the journal Cell Death and Disease, helps determine which therapy will be most effective by testing it directly on living cells, improving personalised therapies.

Eighty-five percent of diagnosed cases of lung cancer are non-small cell lung cancer (NSCLC). In this group, 5% of patients show molecular alterations in the ALK gene involved in cell multiplication. The use of inhibitors against this oncogene — one of the most effective strategies against this type of cancer — has benefited many patients. But, is it possible to know if the treatment will be effective in all those affected?

Now, the functional assay dynamic BH3 profiling (DBP) can predict whether this treatment will be effective in these cancer patients and thus improve personalized therapies. This technique achieves with tumours something very similar to what an antibiogram achieves with a bacterial infection: determining which therapy will be most effective by testing it directly on living cells.​​​​​​​ The technique, which helps to select the best drug for each patient, was patented in 2015 by the Dana-Farber Cancer Institute (Boston, United States) and its co-inventor is Joan Montero, professor at the UB’s Faculty of Medicine and Health Sciences and at the Bioengineering, Biomaterials and Nanomedicine Networking Biomedical Research Centre (CIBER-BBN).

The study is led by Professor Joan Montero, and has as first author the researcher Fernando Martín, member of the UB, the Institute of Bioengineering of Catalonia (IBEC) and the CIBERBBN. Teams from the Faculty of Physics of the UB, the Hospital Clínic, the August Pi i Sunyer Institute of Biomedical Research (IDIBAPS) and the Catalan Institute of Oncology (ICO) also collaborate in the work.

The study, conducted using animal models and patient biopsies, also reveals for the first time that the MCL-1 protein plays a key role in tumour resistance to this type of therapy. It also shows that molecules known as BH3 mimetics can improve the effect of cancer treatments by preventing tumour adaptations to inhibitors of anaplastic lymphoma protein kinase (ALK), one of the main treatments for this cancer.

Predicting the response of the most common lung cancer drugs

Each tumour is unique, and predicting the therapeutic response to non-small cell lung cancer is a breakthrough in personalized medicine. Given this challenge in biomedicine, the study confirms that the dynamic BH3 profiling technique has an excellent predictive capacity for tumour cell response to ALK inhibitors.

ALK inhibitors are used early in disease in patients with non-small cell lung cancer who show molecular alterations in this oncogene. Currently, four generations of ALK inhibitors have been developed with clinical efficacy superior to chemotherapy.

“These targeted therapies confer the longest survival in non-small cell lung cancer and are better tolerated than cytotoxic agents. The use of ALK inhibitors in the clinic not only increases patient survival, but also improves their quality of life”, says Joan Montero, from the UB’s Department of Biomedicine. “In this context, dynamic BH3 profiling could complement the application of genomic assays and mass sequencing that routinely guide the use of these targeted therapies in cancer patients, especially in complex cases”, explains the professor.

How ALK inhibitors work in cancer

In NSCLC patients, a fusion of two genes—ALK and the EML4 gene in 90% of cases—occurs, giving rise to a new gene capable of encoding a mutated protein and activating signaling pathways that promote tumor proliferation. “In their therapeutic action, ALK inhibitors bind specifically to the active site of the chimera protein and prevent its kinase activity. In this way, these drugs inhibit the phosphorylation and activation of other target proteins involved in the growth and survival of tumor cells,” says Fernando Martín, a researcher at the University of Barcelona and IBEC.

Unlike many chemotherapy agents, “ALK inhibitors can cross the blood-brain barrier and reach the central nervous system. Since one-third of patients with advanced NSCLC develop brain metastases, this ability is especially beneficial in the fight against tumors. This type of therapy is also applicable to anaplastic large cell lymphoma and neuroblastoma,” the researcher notes.

Tumor cells that escape death by apoptosis

The study describes for the first time that the anti-apoptotic protein MCL-1 also plays a fundamental role in resistance to these therapies. “One of the main characteristics of therapy-resistant cells is the ability to avoid apoptotic cell death, a cellular mechanism regulated by the BCL-2 protein family. The balance between pro- and anti-apoptotic components ultimately regulates resistance to cell death and adaptation to therapy,” the researchers explain.

Furthermore, the dynamic BH3 profiling technique also allows for the deciphering of antiapoptotic adaptations that arise in response to ALK inhibitors. “These acute adaptations can be prevented with the use of BH3 mimetics (small molecules that inhibit antiapoptotic proteins with high specificity) to improve the treatment effect in vitro and in vivo,” the experts point out.

Among the most immediate future projects, the team will promote new research to determine whether these anti-apoptotic resistances can manifest during longer periods of drug exposure (for example, in therapy-induced senescence). “It would also be very important to determine what proportion of patients could benefit from the use of the dynamic BH3 profiling technique, and from the combination with BH3 mimetics and other drugs against anti-apoptotic proteins,” conclude Joan Montero and Fernando Martín.

» Article of reference: Martín, Fernando; Alcon, Clara; Marín, Elba; Morales-Sánchez, Paula; Manzano-Muñoz, Albert; Díaz, Sherley; García, Mireia; Samitier, Josep; Lu, Albert; Villanueva, Alberto; Reguart, Noemí; Teixidó, Cristina; Montero, 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, marzo de 2025. doi: 10.1038/s41419-025-07513-3

» Link to the news: IBEC website [+] and University of Barcelona [+]