Out-of-frame CBX3::ALK fusion drives ALK activation and therapy response

Hang et al. identify an out-of-frame CBX3::ALK fusion in metastatic melanoma that generates functional ALK isoforms through alternative translation start sites. This study demonstrates that rare noncanonical out-of-frame fusions can be oncogenic and therapeutically actionable, highlighting an analytic blind spot in current gene fusion detection pipelines.