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Novel therapeutic and diagnostic approaches to EML4-ALK-driven cancers

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posted on 2025-02-04, 10:32 authored by Savvas Papageorgiou

EML4-ALK drives progression of ~5% of non-small cell lung cancers and multiple EML4-ALK variants exist as a result of alternative EML4 breakpoints. Of these, V3 is correlated with the most aggressive disease and increased metastasis in patients however, all patients eventually relapse and ultimately develop resistance to ALK inhibitors, the gold-standard approach for ALK+ patients. Unlike other variants, V3 assembles into a complex on interphase microtubules together with the NEK9 and NEK7 kinases, leading to the development of an elongated cell morphology and an enhanced migratory and invasive phenotype. This is the result of the untimely activation of NEK7 and the subsequent microtubule recruitment and phosphorylation of NEK7 substrates such as Eg5 and cortactin.

The main focus of this study was to examine, using two approaches that displace V3 from microtubules, whether microtubule association of V3 is key for the generation of the V3 phenotypes. The data presented here confirm that NEK7 activation drives the generation of the V3 phenotypes and occurs downstream of EML4-ALK. Importantly, removal of V3 from microtubules leads to the dissociation of the downstream proteins from microtubules and the reversal of both V3 phenotypes. Surprisingly, the mitochondrial relocation of V3 identified a possible NEK9-independent interaction between NEK7 and EML4-ALK. Overall, these findings highlight the potential use of the microtubule association of V3 as an alternative therapeutic target for V3 patients.

Finally, the study also led to the development of a non-invasive tandem mass spectrometry-based assay that can detect EML4-ALK variants within blood samples. This is the first of its kind assay that can measure these variants at the peptide level. Hence, it can be proven to be a useful future tool in the clinical setting as a prognostic or predictive assay alongside current diagnostic approaches to facilitate better patient stratification and more personalised treatments.

History

Supervisor(s)

Andrew M. Fry, Donald J.L. Jones

Date of award

2024-12-18

Author affiliation

Department of Molecular and Cell Biology

Awarding institution

University of Leicester

Qualification level

  • Doctoral

Qualification name

  • PhD

Language

en

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