How Hijacking a Cellular Switchboard Could Revolutionize Ovarian Cancer Treatment
Ovarian cancer remains the most lethal gynecologic malignancy, claiming over 15,000 lives annually in the U.S. alone 6 . While cisplatin chemotherapy initially helps 70% of advanced-stage patients, a devastating 80% eventually develop resistance—leading to relapse and few treatment options 4 8 .
This grim reality has fueled a scientific quest to understand why tumors stop responding, and exciting new research points to an unexpected culprit: a protein modification system called neddylation. By targeting this process, scientists are now developing strategies to resensitize tumors to cisplatin, potentially turning the tide against this deadly resistance.
Imagine a bustling command center directing cellular cleanup crews, DNA repair teams, and growth signals. This is essentially the function of Cullin-RING ligases (CRLs), a family of enzymes that tag proteins for destruction.
Their activity depends entirely on neddylation—the attachment of a small protein called NEDD8 to cullin scaffolds.
In ovarian cancer, neddylation goes haywire. Tumors overactivate this system to:
Critically, cisplatin-resistant cells show elevated neddylation activity, creating a self-reinforcing shield against chemotherapy 1 .
Enter MLN4924 (Pevonedistat), a first-in-class inhibitor of the NEDD8-activating enzyme (NAE). This small molecule starves CRLs of NEDD8, causing:
Stabilization of tumor-suppressing proteins
Collapse of repair mechanisms
| Cell Line | Cisplatin Alone (Viability %) | MLN4924 Alone (Viability %) | Combination (Viability %) | Resistance Reversal |
|---|---|---|---|---|
| SKOV3-PR | 85% | 62% | 28% | 3-fold |
| ES2-PR | 92% | 58% | 31% | 3.3-fold |
| Primary HGSOC | 78% | 55% | 33% | 2.7-fold |
Data from resistant cell models shows MLN4924 restores cisplatin sensitivity 2 .
A landmark 2013 study tested MLN4924 in cisplatin-resistant ovarian cancer using a multi-step approach 1 2 :
| Treatment | Tumor Volume Change | Apoptosis Increase | Median Survival |
|---|---|---|---|
| Saline | +142% | Baseline | 32 days |
| Cisplatin alone | -15% | 2.1-fold | 41 days |
| MLN4924 alone | -38% | 3.3-fold | 49 days |
| Combination therapy | -68% | 6.7-fold | 67 days |
Combination doubled survival in resistant models 1 .
| Reagent | Function | Experimental Role |
|---|---|---|
| MLN4924 | Inhibits NEDD8-activating enzyme (NAE) | Blocks neddylation in vitro/in vivo |
| Anti-NEDD8 antibody | Detects neddylated proteins | Western blotting, immunohistochemistry |
| siRNA against Cullins | Silences specific CRL components | Identifies CRL subtypes involved in resistance |
| ROS probes (e.g., DCFDA) | Measures reactive oxygen species | Quantifies oxidative stress in treated cells |
| Cisplatin-DNA adduct ELISA | Detects platinum-DNA damage | Confirms chemotherapy target engagement |
| 3-Hydroxylaurate | C12H23O3- | |
| Sodium octanoate | 1984-06-1 | C8H16NaO2 |
| Verapliquinone C | 109954-47-4 | C17H24O4 |
| ophiopojaponin C | 911819-08-4 | C46H72O17 |
| Verubecestat TFA | 1286770-55-5; 2095432-65-6 | C19H18F5N5O5S |
While neddylation inhibition advances clinically, parallel strategies show promise:
MLN4924 is now in Phase III trials for ovarian cancer, but hurdles remain. Toxicity (notably gastrointestinal effects) requires careful management 6 , and biomarkers to predict responders are urgently needed.
The battle against ovarian cancer resilience is far from over, but by dismantling the neddylation shield, researchers are forging weapons that could finally tip the scales.