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.