Two PVT1 proteins point to new cancer targets in preclinical studies

Under the microscope, tissue samples from prostate, colon, kidney, intestine and breast cancers reveal a recurring molecular story. Teams led by Anindya Bagchi at the Sanford Burnham Prebys Medical Discovery Institute have identified two proteins made from the PVT1 region that can either strengthen or restrain MYC, one of cancer's most frequently altered driver genes.

MYC controls cell growth, division and metabolism. When it becomes overactive, it can push cells toward rapid, uncontrolled tumor growth and treatment resistance. The protein has often been considered difficult to drug because it lacks the typical binding pockets targeted by traditional small-molecule medicines. The new work, published in two back-to-back papers in Genes & Development, points to a different route: interfere with molecules MYC depends on rather than hitting MYC itself.

The first molecule, Firefox, is produced when PVT1 generates a circular RNA that encodes a previously unknown protein. The researchers found that Firefox is essential to MYC-mediated oncogenic signaling. When they depleted Firefox, MYC protein abundance and its transcriptional output declined; in animal models of MYC-driven cancers, the intervention significantly impaired tumor growth.

The second molecule, Honeybadger, acts as a brake. It binds KRAS, whose mutated forms are implicated in roughly 25% to 30% of human cancers, and dampens the RAS-MAPK pathway under normal conditions. When a translocation—a DNA segment moving from one chromosome to another—deletes the part of PVT1 that encodes Honeybadger, that brake disappears. MAPK signaling can then stabilize MYC and increase its cancer-driving output, even without a KRAS mutation.

And so what, concretely? The work offers potential targets for tumors driven by MYC, including cancers that have historically had few direct targeted-treatment options. But the evidence remains preclinical: the studies describe molecular mechanisms and animal models, while the team says it will only now investigate other cancer types and work with collaborators on prototype therapeutic strategies. Firefox and Honeybadger are leads, not available medicines.