One of cancer’s most elusive and tantalizing targets is so common that scientists have given it a nickname: McGene. In 70 percent of cancers, this gene (whose proper name is MYC) is overactive, fueling the aggressive growth, spread, and survival of tumors throughout the body. A study published Friday reveals details about the control circuitry that causes cells to make 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 a glimpse into how to target MYC than a clear path toward a clinical trial testing the strategy in people with cancer. But it highlights the effort to undermine the complicated biology of the gene, which has been seen for decades as a possible Achilles heel for many cancers and as an impossible, “non-drug” target. “I think all roads lead to MYC; no matter how much 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 are mixed with mutations, MYC is a normal gene, without mutations, with its volume very high. There are several ways to put MYC into overdrive, turning it into a “grand orchestrator” that activates a host of molecular switches to give cancer cells the ability to thrive, evade the immune system, and grow uncontrollably. The new study examined one way this happens: the accumulation 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 placing or deleting chemical tags from the genome, they discovered that two switches can modify MYC activity, causing it to accumulate or not accumulate additional copies. It might be easier to target one of those switches, the scientists theorized, than to go after MYC itself. Johnathan Whetstine, director of the Cancer Epigenetics Institute at Fox Chase Cancer Center at Temple Health, who led the work, said these switches are like inserting punctuation into a sentence that significantly changes the meaning. “If you have a sentence, but I put a comma in the right or wrong place or don’t use it at all, I can change the context: ‘Let’s eat, eat, Grandma’ or ‘Let’s eat, Grandma,’” Dr. Whetstine said. One of the switches his team found is an enzyme called KDM4C, which causes the cell’s copying machinery to produce duplicates of MYC. When 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 down, additional copies of MYC accumulated. “The idea for a long time has been that these extra copies of MYC seen in tumors were simply a random result of chaos in cancer cells,” said Laura Soucek, a molecular biologist at the Vall d’Hebron Institute of Oncology and founder of Peptomyc, a company focused on developing drugs to block MYC. The new study, he said, shows that the extra MYC is controlled by a very specific molecular process, with one enzyme, SETD2, a “good guy.” which prevents MYC from amplifying and another, KMD4C, a “bad boy” that causes additional copies to accumulate.Dr. Soucek and other scientists who were not involved in the work cautioned that this was a laboratory study, far from suggesting an immediate therapeutic strategy for patients. While the results shed light on how MYC can become overly abundant in cells, several scientists said, it is not clear to them whether that knowledge has implications for therapeutic efforts targeting MYC once it has been amplified, as it already is when cancer has taken hold. The problem is that it is difficult to stop MYC directly. For decades, MYC has been on a short list 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 adhere to and also contains what scientists call an “intrinsic disordered region” that, like a flexible spaghetti noodle, constantly changes into different loops and shapes that make it difficult to design a drug. Despite those challenges, other efforts are also underway to directly block MYC. along. An early-stage clinical trial published in Nature Medicine in 2024 showed some evidence of antitumor activity from a small protein that directly targets MYC. Other labs are focusing on targeting associated molecules that interact with MYC as an indirect way to block it. A major question looming over the field is whether MYC is too important to the functioning of all cells to be stopped without causing major side effects. “It’s an interesting question: Can you get high?” said Stephen Elledge, a geneticist at Harvard Medical School. “And if you drug him, what is going to happen?”
