Forty years after the mutant genes that cause the deadliest cancers were discovered, drugs that target them could be approved
In the early 1980s, Channing Der was just beginning his career as a scientist at Harvard Medical School when he happened upon a discovery that would change the course of cancer research. At the time, the holy grail of cancer biology was discovering so-called oncogenes – genetic switches that can turn a normal cell into a cancer cell – in the genomes of tumours. But while teams of scientists had thrown everything at it for the best part of a decade, their efforts had proved fruitless. One by one, they were beginning to accept that it might be a dead end.
Der found himself assigned to test 20 different genes that had been identified as possible oncogene candidates. His question was simple: did any of them actually exist in tumours in a form that was different from normal cells?
“People thought it wasn’t going to work,” he remembers. “I began, and certainly for five months, the chances of success seemed to be pretty slim. I was ready to just wrap this up, and move on to something else that might be more productive, when I made the discovery which changed the course of my professional career.”
The first 18 of the genes Der tested turned out to be normal. But the final two, members of a gene family called RAS, were found to be uniquely mutated in cancer cells. “Being fairly new to the field at that point, I didn’t fully understand the ramifications of what this meant,” he laughs. “I was working in the lab of a professor named Geoffrey Cooper, and when I showed him the results, he paused for what seemed like minutes. So I asked if he was OK, and he replied: ‘This could be one of the most significant discoveries in cancer biology in decades.’”
We now know that about 20% of all cancers harbour a mutation in one of three RAS genes; KRAS, HRAS and NRAS. Each of these genes directs the production of a protein that naturally flexes and relaxes, on and off, thousands of times a second. In the “on” position, it allows cells to grow, and then in the “off” setting, it stops the growth. However, when the RAS genes are mutated, the protein remains stuck in its on state, and the cell is forced to proliferate out of control, becoming a tumour. Of the three genes, KRAS is the most notorious, as its mutant forms are commonly found in some of the deadliest cancers. KRAS mutations occur in up to 96% of pancreatic cancers, and 54% of colorectal cancers.
Over the past 40 years, the pharmaceutical industry has repeatedly tried to find a way to switch RAS proteins off in cancer cells. It has been a long journey, checkered with abandoned hopes, and hundreds of millions lost in failed trials. But over the past eight years, a breakthrough has breathed new light into the field. At least eight companies now have drugs in clinical development that appear to successfully target a KRAS mutant. If all goes to plan in 2021, they could soon be approved by regulators, paving the way for a whole new class of cancer medicines.