At a conference in Chicago at the end of May oncologists went wild over the results of a drug called daraxonrasib, which treats pancreatic cancer.
Pancreatic cancers are aggressive and usually symptomless.
The mutation in the KRAS protein, which drives most pancreatic cancers, creates an environment outside each tumour that is hostile to immune cells.
Stopping KRAS in pancreatic cancer will help in other tumours where the same mutation drives the disease, such as some colorectal and lung cancers and, to a lesser degree, in endometrial, small bowel and stomach cancers.
Tackling one cancer has, potentially, revealed a master switch that enables new treatments for millions of people.
Scientists are not usually an excitable bunch. So when many thousands of them recently gave a spontaneous standing ovation (with cheering) in the middle of a lecture, it meant something special happened. At a conference in Chicago at the end of May oncologists went wild over the results of a drug called daraxonrasib, which treats pancreatic cancer. The drug almost doubled median survival times from 6.7 months to 13.2 months. This victory over one of the most challenging cancers was an emotional moment for some. Photograph: Cristina Spanò
The drug isn’t anything close to a cure. Cancers often develop resistance to targeted drugs such as daraxonrasib. The drug’s promise for patients is that, when used alongside other treatments, it might open the door to much longer survival times. Pancreatic cancers are aggressive and usually symptomless. They are usually diagnosed after they have already spread around the body. Few patients survive longer than a year, and this cancer had also turned out to be resistant to immunotherapy, a class of treatment that deploys the body’s immune system to fight tumours and which has been such a lifeline in many other cancers. The mutation in the KRAS protein, which drives most pancreatic cancers, creates an environment outside each tumour that is hostile to immune cells.
The drug is expected to speed its way through approval in America. Eventually it seems likely to be given as a first-line treatment—rather than to those who have already tried chemotherapy, as was the case in the trial. The drug works by inhibiting KRAS. Other work suggests this also changes the environment around the tumour in ways that mean the tumour may respond to immunotherapy. If this approach is successful, it could further improve survival times.
There is a bigger story. By solving the puzzle of how to inhibit signals from KRAS mutant tumours, the researchers have tackled a critical pathway that is found in many different cancers. KRAS is a molecular switch in the cell with an off and on state. A single mutation can leave the KRAS protein jammed on, endlessly signalling to cells that they should divide. Stopping KRAS in pancreatic cancer will help in other tumours where the same mutation drives the disease, such as some colorectal and lung cancers and, to a lesser degree, in endometrial, small bowel and stomach cancers.
What is more, KRAS is just one of a family of oncogenes that are collectively known as RAS mutations. Daraxonrasib could, in theory, work on other RAS-driven cancers to some degree—such as multiple myeloma. All told, RAS mutations are found in 20% of all cancers and in 3.4m cases of cancer globally every year. Little wonder that RAS has been a key target for oncologists since their discovery in 1982. But for four decades it was the white whale of oncology. Because it has a structure that some described as smooth like a golf ball there was no molecular chink with which to attack it and scientists deemed it “undruggable”. Until it wasn’t. In the end they found daraxonrasib, a small molecule that works as a “molecular glue” with another cellular protein to prevent RAS proteins from signalling.
This is just the beginning—more refined versions of the drug, and follow-on competitors, will come later. There is even hope these drugs might help an entirely different group of cancer patients: children with neuroblastoma, where a different mutation disables a gene that normally acts as a brake on RAS. Tackling one cancer has, potentially, revealed a master switch that enables new treatments for millions of people. Daraxonrasib deserves its standing ovations.
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