Personalized lung cancer therapy: Predicting ALK inhibitor response

A team of researchers from the University of Barcelona (UB), in collaboration with various Spanish research institutions, has shown that the functional assay dynamic BH3 profiling (DBP) can help predict whether patients with non-small cell lung cancer (NSCLC) will respond to ALK inhibitor therapies. This technique could serve as a complementary tool in personalizing cancer treatments. 

Non-small cell lung cancer accounts for 85 percent of all lung cancer diagnoses. Around 5 percent of NSCLC patients show molecular alterations in the ALK gene, which is involved in cell proliferation. In these cases, ALK inhibitors have become standard treatment. Four generations of these inhibitors have been developed to date, offering higher efficacy and tolerability than traditional 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 Faculty of Medicine and Health Sciences and CIBER-BBN. 

Dynamic BH3 profiling works similarly to an antibiogram, but for tumour cells – helping identify effective therapies by testing their impact on living cells. The technique was originally patented in 2015 by the Dana-Farber Cancer Institute, with Montero as co-inventor. 

This recent study, published in Cell Death and Disease, included data from both animal models and patient biopsies. The results highlight DBP’s ability to predict how tumor cells respond to ALK inhibitors and identify resistance mechanisms. 

The research also revealed that the anti-apoptotic protein MCL-1 plays a key role in therapy resistance. Cancer cells that survive treatment often evade apoptosis, the body’s natural mechanism for eliminating damaged cells. 

“One of the key features of therapy-resistant cells is the ability to avoid apoptotic cell death,” explain the researchers. To counter this resistance, BH3 mimetics – small molecules that target anti-apoptotic proteins – can be used. For example, Venetoclax (a BCL-2 inhibitor) is already in clinical use, while MCL-1 inhibitors are being studied in trials. The authors propose using BH3 mimetics in combination with ALK inhibitors to strengthen therapeutic outcomes. 

“Our study also proposes alternatives to the use of BH3 mimetics to indirectly but effectively inhibit these proteins and substantially enhance the effect of ALK inhibitors,” say Montero and Fernando Martín, lead author of the study. 

MEDICA-tradefair.com; Source: Universidad de Barcelona