A novel MYO5C-ALK fusion in lung adenocarcinoma: limited alectinib response and durable lorlatinib benefit.
A novel MYO5C-anaplastic lymphoma kinase fusion showed durable response to lorlatinib.
A novel MYO5C-ALK fusion in lung adenocarcinoma: limited alectinib response and durable lorlatinib benefit.
Anaplastic lymphoma kinase (anaplastic lymphoma kinase) rearrangements drive approximately 5% of non-small cell lung cancers (non-small cell lung cancers), most commonly as EML4-anaplastic lymphoma kinase, but rare 5' partners may confer distinct pharmacologic behaviour.
Diagnosis and resistance profiling used DNA- and RNA-based next-generation sequencing (next-generation sequencing), immunohistochemistry (immunohistochemistry) and serial imaging.
A 72-year-old never-smoker with stage IVB lung adenocarcinoma harboured an in-frame MYO5C-anaplastic lymphoma kinase fusion retaining the entire anaplastic lymphoma kinase tyrosine kinase domain.
We hypothesise that constitutive, partner-driven dimerisation of the MYO5C-anaplastic lymphoma kinase 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.
This first report of a MYO5C-anaplastic lymphoma kinase fusion proposes a hypothesised biological rationale - partner-driven dimerisation overcome by a more potent macrocyclic inhibitor - for the differential anaplastic lymphoma kinase-inhibitor response, and supports lorlatinib for atypical fusions and for mutation-negative second-generation tyrosine kinase inhibitor (tyrosine kinase inhibitor) resistance.