EML4-ALK V3 Drives Cell Migration Through NEK9 and NEK7 Kinases in Non-Small-Cell Lung Cancer

Abstract

EML4-ALK is an oncogenic fusion present in ~5% lung adenocarcinomas. However, alternative breakpoints in the EML4 gene lead to distinct variants with different patient outcomes. Here, we show that EML4-ALK variant 3, which is linked to accelerated metastatic spread and worse patient outcome, causes microtubule stabilization, formation of extended cytoplasmic protrusions, loss of cell polarity and increased cell migration. Strikingly, this is dependent upon the NEK9 kinase that interacts with the N-terminal microtubule-binding region of EML4. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates cell migration in a manner that requires the downstream kinase NEK7 but not ALK activity. Moreover, elevated NEK9 is associated with EML4-ALK V3 expression as well as reduced progression-free and overall survival in patients. Hence, we propose that EML4-ALK V3 promotes microtubule recruitment of NEK9 and NEK7 to increase cell migration and that this represents an actionable pathway that drives disease progression in lung cancer.