Targeting the HEC1-NEK2 Axis Suppresses DLBCL Progression and Overcomes Vincristine Resistance.

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive subtype of non-Hodgkin lymphoma (NHL), in which resistance to microtubule-targeting agents (MTAs) such as vincristine (VCR) remains a major therapeutic challenge. HEC1 (highly expressed in cancer 1) and NEK2 (NIMA-related kinase 2) are mitotic regulators that cooperate to maintain spindle integrity. Although HEC1 inhibitors that disrupt the HEC1-NEK2 interaction have been proposed as alternatives to MTAs with reduced neurotoxicity, their therapeutic relevance in DLBCL remains unknown. Here, we show that HEC1 and NEK2 are concomitantly upregulated in DLBCL, and their aberrant expression is associated with poor prognosis across multiple patient cohorts. The promoters of HEC1 and NEK2 show extensive sequence homology, and both genes are co-regulated by a shared transcriptional network including cell cycle-related transcription factors (TFs), involving FOXM1, MYC, and E2F family members, highlighting the central role of NEK2 in mitotic regulation together with the NDC80 complex. The HEC1 inhibitor TAI-1, which disrupts the HEC1-NEK2 interaction, induced degradation of HEC1 and NEK2, promoted GSK3β-dependent phosphorylation and degradation of β-catenin, and significantly suppressed DLBCL growth through mitotic catastrophe-associated apoptosis. Notably, HEC1 and NEK2 were upregulated in VCR-resistant DLBCL cells, and TAI-1 treatment restored VCR sensitivity and showed synergistic effects in combination with VCR. Our findings identify the HEC1-NEK2 axis as a therapeutic vulnerability in DLBCL and support combining HEC1 inhibitors with MTA-based chemotherapy to achieve superior anti-DLBCL efficacy.