How targeting NEK9 flips cancer cell fate — from survival to explosive death             
By Shamima Azma Ansari & Rupesh Dash

🚨 The Problem: When Chemotherapy Stops Working

Chemotherapy often starts strong but hits a wall—tumours adapt, resist, and fight back. For some cancers, resistance is baked in from the start. Should we give up? Or can we outsmart cancer by finding its weakest link?

🔍 Hunting Resistance Genes with a Kinome-Wide Screen

To uncover what’s behind this resistance, we ran a CRISPR/Cas9 screen targeting 840 kinase genes in cancer cells. The goal? Find which genes protect tumours from docetaxel, a common chemotherapy drug.

The standout? NEK9.

🎯 NEK9: From Mitosis Regulator to Chemoresistance Gatekeeper

NEK9 is known for its role in cell division and spindle assembly—but docetaxel resistance? That was new.

Our key findings:

• NEK9 levels are higher in tumours from patients who respond poorly to chemotherapy.
• Knocking out NEK9 made cancer cells dramatically more sensitive to docetaxel.

NEK9 emerged as a molecular switch dictating whether cancer cells live or die during treatment.

 💥 The Twist: Losing NEK9 Sparks Pyroptosis — Fiery Cell Death

Deleting NEK9 and treating cells with docetaxel didn’t just increase death—it changed how cells died.

Pyroptosis is a fiery, inflammatory form of cell death. Unlike quiet apoptosis, pyroptosis causes cells to swell, burst, and release signals that rally the immune system.

Why does this matter?

• It flags tumours for immune attack.
• It supercharges tumour destruction.

🧬 The Mechanism: How NEK9 Controls the Wnt Signaling Brake

Here’s the surprise connection: NEK9 keeps a protein called TLE3 in check. TLE3 is a brake on the Wnt signaling pathway, which helps cancer cells survive chemotherapy.

Without NEK9:

• TLE3 floods in, slamming the brakes on Wnt signaling.
• Wnt shutdown strips cancer cells of their survival tools.
• Cells become vulnerable to pyroptosis—a fiery, inflammatory death.

🧩 The Bigger Picture: NEK9, Wnt Signaling, and Tumour Survival

Our data suggest this model:

• NEK9 suppresses TLE3 → Wnt signaling stays ON → cells resist chemotherapy.
• Loss of NEK9 → TLE3 rises → Wnt signaling OFF → pyroptosis triggered → cancer cells die.

🔥 Why Pyroptosis Matters in Cancer Therapy

Most chemotherapies aim to trigger apoptosis. But tumours often block this silent death to survive.

Pyroptosis offers a powerful detour:

• It kills cancer cells explosively.
• It recruits immune cells via inflammation.
• It could turn “cold” tumours into “hot,” more treatable ones.
• It might prevent cancer from coming back.

“It’s not just about killing cancer cells—it’s about how we kill them, and the signals we send to the body.”

💊 A Potential Therapy: Repurposing Fostamatinib to Target NEK9

Could we drug NEK9?

By screening kinase inhibitors, we identified fostamatinib, an FDA-approved drug for immune disorders, as an NEK9 inhibitor.

Combining fostamatinib with docetaxel:

• In cell cultures: Boosted cancer cell death.
• In mouse models: Significantly slowed tumour growth.

💬 Final Thoughts

Our study shows that overcoming resistance isn’t just about killing more cancer cells—it’s about changing how they die.

By removing NEK9’s suppression of pyroptosis, we can give chemotherapy a powerful new edge, making it harder for cancer to survive and hide.

We’re excited about the potential of this approach to create smarter, longer-lasting cancer treatments.