blood-cancer

Repurposed cancer drug OTS167 targets newly discovered mitotic kinase in aggressive lymphoma, showing tumor reduction in mice

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma, and many patients aren't cured by standard treatment. Researchers screened a library of kinase inhibitors and stumbled onto an unexpected target: GAK (cyclin G-associated kinase), a protein previously thought to mainly help cells manage membrane traffic.

It turns out GAK plays a critical role in cell division in DLBCL — specifically in the mitotic phase, when cells split in two. When GAK is inhibited, cancer cells get stuck mid-division, chromosomes go haywire, and the cells essentially self-destruct. Importantly, this effect was selective for cancer cells and didn't harm normal cells.

The team also found that tumors with loss of the RB1 gene — a common event in DLBCL — are especially dependent on GAK. A drug called OTS167, already in development for solid tumors, turns out to potently inhibit GAK and shrank tumors in a mouse model derived from a human DLBCL patient. This suggests a fast path to clinical use through drug repurposing.

Key Findings

GAK is a novel mitotic kinase in DLBCL, not previously known to regulate cell division
GAK inhibition causes G2/M arrest, spindle distortion, and chromosomal damage in DLBCL cells but not normal cells
RB1-deficient DLBCL cells are especially sensitive to GAK inhibition — RB1 loss is a common but undruggable DLBCL driver
OTS167, an approved-pathway drug targeting MELK, potently inhibits GAK and reduced tumor burden in a patient-derived xenograft mouse model
GAK expression correlates with RB1 deficiency in clinical DLBCL samples, identifying a potential patient selection biomarker

Implications

This work identifies GAK as a druggable target in DLBCL, particularly for patients with RB1 loss-of-function — a group with no targeted therapies. Because OTS167 already inhibits GAK potently and has been tested in humans, clinical trials in DLBCL could potentially move quickly. The RB1 biomarker could help select patients most likely to respond.

Caveats

Preprint — not yet peer reviewed. In vivo data is from a single patient-derived xenograft model; broader validation is needed. No GAK-selective clinical inhibitor exists yet — OTS167's effects may involve other targets. Translating mouse xenograft results to human trials has a high failure rate.

Source: bioRxiv — 2026-04-06

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