Papageorgiou Cancer Review 2022.pdf (10.4 MB)
Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer
journal contributionposted on 2022-09-09, 10:27 authored by Savvas Papageorgiou, Sarah L Pashley, Laura O'Regan, Sam Khan, Richard Bayliss, Andrew M Fry
EML4-ALK is an oncogenic fusion protein that accounts for approximately 5% of NSCLC cases. Targeted inhibitors of ALK are the standard of care treatment, often leading to a good initial response. Sadly, some patients do not respond well, and most will develop resistance over time, emphasizing the need for alternative treatments. This review discusses recent advances in our understanding of the mechanisms behind EML4-ALK-driven NSCLC progression and the opportunities they present for alternative treatment options to ALK inhibitor monotherapy. Targeting ALK-dependent signalling pathways can overcome resistance that has developed due to mutations in the ALK catalytic domain, as well as through activation of bypass mechanisms that utilise the same pathways. We also consider evidence for polytherapy approaches that combine targeted inhibition of these pathways with ALK inhibitors. Lastly, we review combination approaches that use targeted inhibitors of ALK together with chemotherapy, radiotherapy or immunotherapy. Throughout this article, we highlight the importance of alternative breakpoints in the EML4 gene that result in the generation of distinct EML4-ALK variants with different biological and pathological properties and consider monotherapy and polytherapy approaches that may be selective to particular variants.
Author affiliationDepartment of Molecular and Cell Biology, University of Leicester
- VoR (Version of Record)
Science & TechnologyLife Sciences & BiomedicineOncologyEML4-ALKNSCLCALK inhibitorsTKIschemotherapyradiotherapyimmunotherapymicrotubule poisonsANAPLASTIC LYMPHOMA KINASEMUTATION CONFERS RESISTANCEPOLYMERASE CHAIN-REACTIONACQUIRED-RESISTANCEOPEN-LABELFUSION VARIANTCRIZOTINIB RESISTANCEPOLYTHERAPY STRATEGYTARGETED THERAPYDRUG-RESISTANCE