PNKP Inhibition exploits vulnerabilities in tumors
- Martin Döhring
- 29. Sept.
- 1 Min. Lesezeit
NKP inhibition exploits vulnerabilities in tumors with deficiencies in tumor suppressor genes like PTEN (Phosphatase and Tensin Homolog) or SHP-1 (Src Homology Phosphatase 1, also known as PTPN6). PTEN regulates the PI3K/AKT pathway and DNA repair; its loss makes cells reliant on PNKP for survival. Similarly, SHP-1 dephosphorylates signaling proteins to inhibit cell growth; its deficiency creates a dependency on PNKP. Co-inhibition or deficiency leads to catastrophic DNA damage, selectively killing cancer cells without affecting healthy ones.
PNKP inhibitors are emerging as a powerful tool in cancer therapy by exploiting synthetic lethality—a strategy that targets cancer-specific vulnerabilities while sparing healthy cells. Here's how they work:
What Is PNKP?
Polynucleotide Kinase 3′-Phosphatase (PNKP) is a DNA repair enzyme that:
Fixes single-strand breaks (SSBs) in DNA.
Works with other repair proteins like XRCC1 and DNA ligase III.
Is essential for maintaining genomic stability.
How PNKP Inhibitors Exploit Cancer Vulnerabilities
1. Targeting Tumor Suppressor Deficiencies
Certain cancers lose key tumor suppressor genes like:
PTEN: Regulates the PI3K/AKT pathway and DNA repair.
SHP-1 (PTPN6): Controls cell signaling and growth inhibition.
When these genes are mutated or deleted:
Cancer cells become hyper-reliant on PNKP for survival.
Inhibiting PNKP in these cells causes…