A novel MYO5C-ALK fusion in lung adenocarcinoma: limited alectinib response and durable lorlatinib benefit.

OBJECTIVES

Anaplastic lymphoma kinase (ALK) rearrangements drive approximately 5% of non-small cell lung cancers (NSCLC), most commonly as EML4-ALK, but rare 5' partners may confer distinct pharmacologic behaviour. We report the first lung adenocarcinoma harbouring a novel MYO5C (exon 23)-ALK (exon 20) fusion.

MATERIALS AND

METHODS

Diagnosis and resistance profiling used DNA- and RNA-based next-generation sequencing (NGS), immunohistochemistry (IHC) and serial imaging. In silico molecular docking of alectinib and lorlatinib against the patient-derived fusion kinase was performed with AutoDock Vina.

RESULTS

A 72-year-old never-smoker with stage IVB lung adenocarcinoma harboured an in-frame MYO5C-ALK fusion retaining the entire ALK tyrosine kinase domain. The tumour progressed at approximately seven months on first-line alectinib despite re-biopsy showing no acquired ALK kinase-domain mutation, no TP53 mutation or bypass alteration (mutation-negative resistance), then achieved a durable partial response to lorlatinib (progression-free survival > 15 months). We hypothesise that constitutive, partner-driven dimerisation of the MYO5C-ALK chimera may sustain kinase signalling that alectinib incompletely suppresses, whereas the higher potency and macrocyclic rigidity of lorlatinib could restore durable inhibition of the structurally intact kinase. In silico docking is consistent with this hypothesis, showing a preserved ATP-binding pocket and a more extensively anchored binding mode for lorlatinib concordant with the known potency differential.

CONCLUSION

This first report of a MYO5C-ALK fusion proposes a hypothesised biological rationale - partner-driven dimerisation overcome by a more potent macrocyclic inhibitor - for the differential ALK-inhibitor response, and supports lorlatinib for atypical fusions and for mutation-negative second-generation tyrosine kinase inhibitor (TKI) resistance.