Scientists discover how to control MYC cancer gene amplification

A study published in Molecular Cell on October 2, 2026, reveals how scientists at Fox Chase Cancer Center controlled the amplification of the common, "undruggable" cancer gene MYC. By targeting the epigenetic machinery—specifically the gatekeeper proteins KDM4C and SETD2—rather than the MYC protein itself, researchers successfully stopped gene copy-number amplification in cell and animal models. This discovery offers a potential therapeutic pathway for treating aggressive, drug-resistant cancers.

MYC gene amplification control

• ▪Blocking the activity of the protein KDM4C, either genetically or with targeted drugs, reduced MYC gene amplification in cancer cells and animal models in a Fox Chase Cancer Center study.
• ▪The MYC gene is overactive in 70 percent of human cancers, driving aggressive tumor growth, but has been considered "undruggable" for over 40 years due to its lack of a physical binding pocket.
• ▪A Fox Chase Cancer Center study published in Molecular Cell on October 2, 2026, revealed that MYC gene copy-number amplification is a biologically regulated process controlled by epigenetic machinery rather than a random mutation.
• ▪Researchers at the Cancer Epigenetics Institute at Fox Chase Cancer Center bypassed the undruggable nature of the MYC protein by targeting the DNA structural assembly line that controls gene amplification.

Epigenetic regulation mechanisms

• ▪Researchers at Fox Chase Cancer Center identified specific enzymatic "kill switches" within chromatin architecture that regulate targeted gene amplification.
• ▪Directing the chromatin-regulating protein KDM4C to the MYC gene region using dCas9 technology triggered gene amplification in cells with normal chromosomes in a Fox Chase Cancer Center study.
• ▪A Fox Chase Cancer Center study found that epigenetic imbalance can directly trigger MYC gene amplification and drive its progression into aggressive forms like circular extrachromosomal DNA.

KDM4C protein gatekeeper role

• ▪A clinically used KDM4 inhibitor successfully suppressed MYC gene amplification in vivo in animal models during a Fox Chase Cancer Center study.
• ▪Tumors increase levels of the KDM4C protein, which alters the surrounding DNA environment and drives harmful MYC gene amplifications.
• ▪The chromatin-regulating protein KDM4C acts as a gatekeeper that, when improperly regulated, recruits DNA-copying machinery to repeatedly copy the MYC gene.

SETD2 protein gatekeeper role

• ▪The chromatin-regulating protein SETD2 normally helps keep DNA stable and strictly regulated within cells, acting as a gatekeeper against MYC gene amplification.
• ▪When the SETD2 protein is blocked or lost, the KDM4C protein can improperly access the MYC gene region to trigger amplification.

Tumor evolution resistance patterns

• ▪The loss of the tumor suppressor gene TP53, combined with disrupted epigenetic control, allows abnormal MYC amplifications to survive, reach high levels, and promote tumor formation.
• ▪A Fox Chase Cancer Center study suggests MYC amplification develops in stages, starting with chromatin regulation changes followed by the failure of cellular defense systems.
• ▪While MYC overactivation normally triggers programmed cell death as a safeguard, disabling this cellular fail-safe allows hyperamplification and tumor formation to occur.

Debatable claims

• ▪The concept of 'undruggable' proteins is an outdated paradigm in oncology
• ▪Targeting epigenetic regulators is more viable than targeting the MYC protein directly