Gene Mix-Up and Cancer's Drug Defense

Cancer is a tricky foe, always finding ways to dodge treatments. One type, Ewing sarcoma, often affects young people. It's caused by a gene fusion called EWS::FLI1. This fusion acts like a commander, driving cancer cells to multiply uncontrollably. Scientists made a surprising find. EWS::FLI1 disrupts the normal untangling of DNA knots, called R-loops. It does this by holding back a helper protein, DHX9. This protein usually helps untangle these knots. When EWS::FLI1 interferes, the knots pile up. This makes cancer cells more vulnerable to certain drugs. These drugs target an enzyme called topoisomerase 1, which usually helps untangle DNA. But there's a catch. If there's too much DHX9 or too little EWS::FLI1, the cancer cells become resistant to these drugs. This resistance isn't about how fast the cancer cells grow or how many other proteins they produce. It's all about the balance between EWS::FLI1 and DHX9. This discovery is crucial. It shows how a single genetic change can greatly affect how cancer cells respond to treatment. It also explains why some patients with high DHX9 levels don't respond well to treatment. This new insight could lead to improved strategies for fighting Ewing sarcoma and other cancers.