One of the most elusive and tantalizing targets in cancer is so common that scientists have a nickname for it: McGene.
In 70 percent of cancers, this gene — whose proper name is MYC — is too active and fuels the aggressive growth, spread and survival of tumors all over the body. A study published on Friday reveals details about the control circuit that triggers cells to churn out extra copies of MYC — offering a new and potentially more tractable target for drugs.
The study, published in the journal Molecular Cell, is basic science, more of a glimmer about how to target MYC than a clear path to a clinical trial that tests the strategy in people with cancer. But it highlights the effort to chip away at the complicated biology of the gene, which has been seen for decades as both a potential Achilles’ heel for many cancers and an impossible, “undruggable” target.
“I think all roads lead to MYC; however hard you try to ignore it — it’s there,” said Dr. Marc Mansour, a hematologist and cancer researcher at University College London who was not involved in the study.
Unlike other genes that drive cancer after they get jumbled with mutations, MYC is a normal gene — no mutations — with its volume turned way up. There are several ways to send MYC into overdrive, turning it into a “grand orchestrator” that flips a vast number of molecular switches to give cancer cells the ability to thrive, dodge the immune system and grow out of control.
The new study examined one way this happens: the buildup of extra gene copies.
Scientists at Fox Chase Cancer Center in Philadelphia first focused on the molecular machinery that orchestrates which genes are active. By attaching or erasing chemical tags from the genome, they found that two switches can tweak MYC activity, causing extra copies to accumulate or not. It might be easier to target one of those switches, the scientists theorized, than to go after MYC itself.
Johnathan Whetstine, the director of the Cancer Epigenetics Institute at Fox Chase Cancer Center at Temple Health who led the work, said to think of these switches as inserting punctuation into a sentence that significantly changes the meaning.
“If you have a sentence, but I place a comma in the right or wrong place or don’t use it, I can change the context: ‘Let’s eat, comma, grandma,’ or ‘Let’s eat grandma,’” Dr. Whetstine said.
One of the switches his team found is an enzyme called KDM4C, which prompts the copying machinery of the cell to make duplicates of MYC. When the scientists administered an experimental drug to block KDM4C in cells in a dish and in mice, the number of extra copies decreased. They also identified another genetic switch, SETD2, but this one keeps MYC in check. When they shut it off, extra copies of MYC accumulated.
“The idea for a very long time has been these extra copies of MYC observed in tumors were just a random result of chaos in cancer cells,” said Laura Soucek, a molecular biologist at Vall d’Hebron Institute of Oncology and a founder of Peptomyc, a company focused on developing drugs to block MYC.
The new study, she said, shows that extra MYC is controlled by a very specific molecular process — with one enzyme, SETD2, a “good guy” that stops MYC from amplifying and another, KMD4C, a “bad guy” that causes extra copies to pile up.
Dr. Soucek and other scientists not involved in the work cautioned that this was a laboratory study, far from suggesting an immediate therapeutic strategy for patients. While the results shine a light on how MYC may become overabundant in cells in the first place, several scientists said, it is unclear to them whether that knowledge has implications for therapeutic efforts to target MYC once it’s amplified, as it already is when cancer has taken hold.
The problem is that MYC is difficult to stop directly. For decades, MYC has been on a shortlist of “most wanted” cancer targets, along with KRAS — a gene that is mutated in most cases of pancreatic cancer.
MYC lacks pockets and crevices for drugs to attach to and also contains what scientists call an “intrinsic disordered region” that, like a floppy spaghetti noodle, constantly shifts into different loops and shapes that make it hard to design a drug.
Despite those challenges, other efforts to directly block MYC are also moving along. An early-stage clinical trial published in Nature Medicine in 2024 showed some evidence of anti-tumor activity from a small protein that directly targets MYC. Other labs are focusing on targeting the partner molecules that interact with MYC as an indirect way to block it.
A major question hanging over the field is whether MYC is too central to how all cells function to be stopped without causing major side effects.
“It’s an interesting question, as to — can you drug it?” said Stephen Elledge, a geneticist at Harvard Medical School. “And if you drug it, what’s going to happen?”
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