When two genes go missing in cancer, a powerful growth switch gets stuck in the ‘on’ position
Researchers have found that two genes that normally put a brake on cell growth are lost in many cancers — and that their loss unleashes one of the most well-known growth molecules…
The genes are called ZNRF3 and RNF43. They produce proteins that act as cellular gatekeepers: they tag excess surface receptors for degradation, keeping growth signals in check. Until now, their best-known role was regulating the WNT signaling pathway — a communication channel between cells that is essential during development but frequently misfires in cancer.
But a new study published in eLife shows that ZNRF3 and RNF43 also control the receptor for another major growth signal: EGFR, the epidermal growth factor receptor. EGFR is one of the most studied proteins in oncology — it’s already the target of multiple cancer drugs, including cetuximab and erlotinib. When ZNRF3 and RNF43 are lost in a tumor cell, EGFR accumulates at the cell surface. The result: the cell receives a constant, powerful growth signal, as if the accelerator is stuck.
Why this matters for cancer therapy
EGFR-targeting drugs are already in clinical use, but they don’t work for all patients. Some of that variability is explained by mutations in EGFR itself or in downstream signaling proteins like RAS. But this research suggests that loss of ZNRF3 or RNF43 represents a distinct mechanism by which EGFR signaling goes wrong — one that standard testing doesn’t always detect.
The clinical implications are direct. Patients whose tumors have lost ZNRF3 or RNF43 might benefit from EGFR inhibitors, even if their tumors were not previously classified as EGFR-driven. Conversely, this may explain why some patients fail to respond to WNT-targeted therapies: the disruption extends beyond the WNT pathway alone.
The connection to aging biology
For longevity science, this research is relevant for a broader reason. Cancer is fundamentally a disease of aged DNA and dysregulated cell control, and the risk of cancer rises exponentially with age. ZNRF3 and RNF43 are part of the quality control system cells use to prevent runaway growth. As that system degrades over time — through accumulating mutations, epigenetic changes, or declining DNA repair capacity — the likelihood of these loss events increases.
Understanding how these molecular gatekeepers fail is therefore not only relevant for cancer treatment. It’s part of understanding what cellular aging actually means at a mechanistic level.