University of Leicester
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Alternative Treatment Options to ALK Inhibitor Monotherapy for EML4-ALK-Driven Lung Cancer

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journal contribution
posted 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.

History

Author affiliation

Department of Molecular and Cell Biology, University of Leicester

Version

  • VoR (Version of Record)

Published in

CANCERS

Volume

14

Issue

14

Publisher

MDPI

issn

2072-6694

eissn

2072-6694

Acceptance date

2022-07-12

Copyright date

2022

Available date

2022-09-09

Spatial coverage

Switzerland

Language

English