Detecting Resistance to Therapeutic ALK Inhibitors in Tumor Tissue and Liquid Biopsy Markers: An Update to a Clinical
Paul Hofman1,2
1Laboratory of Clinical and Experimental Pathology, Université Côte d'Azur, CHU Nice, FHU OncoAge, Pasteur Hospital, 30 Avenue de la Voie Romaine, BP69, CEDEX 01, 06001 Nice, France.
Abstract:
The survival of most patients with advanced stage non-small cell lung cancer is prolonged by several months when they are treated with first- and next-generation inhibitors targeting ALK rearrangements, but resistance inevitably emerges. Some of the mechanisms of resistance are sensitive to novel ALK inhibitors but after an initial tumor response, more or less long-term resistance sets in. Therefore, to adapt treatment it is necessary to repeat biological sampling over time to look for different mechanisms of resistance. To this aim it is essential to obtain liquid and/or tissue biopsies to detect therapeutic targets, in particular for the analysis of different genomic alterations. This review discusses the mechanisms of resistance to therapeutics targeting genomic alterations in ALK as well as the advantages and the limitations of liquid biopsies for their identification.
Insights
Treatment for advanced non-small cell lung cancer (NSCLC) with ALK inhibitors is effective but resistance occurs. Repeated biopsies, including liquid biopsies, are crucial for identifying new resistance mechanisms and adapting therapy.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Advanced non-small cell lung cancer (NSCLC) patients treated with anaplastic lymphoma kinase (ALK) inhibitors show improved survival.
- Resistance to ALK inhibitors inevitably develops, necessitating ongoing treatment adaptation.
- Understanding resistance mechanisms is key to overcoming therapeutic limitations.
Purpose of the Study:
- To review the mechanisms of resistance to ALK-targeted therapies in NSCLC.
- To discuss the utility of liquid biopsies in identifying resistance mechanisms.
- To highlight the advantages and limitations of liquid biopsies for therapeutic target detection.
Main Methods:
- Literature review of studies on ALK inhibitors in NSCLC.
- Analysis of resistance mechanisms associated with ALK genomic alterations.
- Evaluation of liquid biopsy techniques for detecting genomic alterations and resistance markers.
Main Results:
- Multiple resistance mechanisms to ALK inhibitors exist, some targetable by newer agents.
- Tumor response to novel ALK inhibitors can be transient, followed by acquired resistance.
- Liquid biopsies offer a less invasive method for serial monitoring of genomic alterations.
Conclusions:
- Repeated biological sampling, particularly liquid biopsies, is essential for identifying evolving resistance mechanisms in ALK-mutated NSCLC.
- Liquid biopsies provide valuable insights into genomic alterations, aiding in personalized treatment strategies.
- Further research is needed to optimize the use of liquid biopsies in clinical practice for NSCLC management.
