Pursuing the 'Impossible': A Pancreatic Cancer Breakthrough

The headline in the May 12, 2026 New York Times article, written by Gina Kolata and Rebecca Robbins, tells it all: How an 'Impossible' Idea Led to a Pancreatic Cancer Breakthrough. Incredibly important discoveries can come from ideas that seem impossible at the start. If only 'sure things' were pursued innovation would wither.

People with pancreatic cancer desperately need innovation. The disease is usually diagnosed after it has spread, and kills over 50,000 Americans per year. Yet every attempt to conquer the cancer has met with failure--research hitting dead ends and even more crushingly, clinical trials missing their goals.

The science seems clear: figure out how to stop KRAS, a protein whose mutated state in pancreatic cancer leads to uncontrolled growth in cells. But KRAS, described as a "greasy ball" in the article, seemed to be 'impossible' to drug. Researchers tried, and failed, and eventually turned their efforts to other avenues.

But Dr. Kevan Shokat kept at it. Drawing on decades of knowledge built up with the support of the National Institutes of Health, and the Howard Hughes Medical Institute, he spent five years screening 500 compounds in the 'impossible' task of finding a crack in KRAS armor, and finally, it appeared--upending the long-established 'fact' that pursuing KRAS was a dead end.

It wasn't the final answer--it took a combination of industry determination and some glue! to get to the drug that may give thousands of patients more time in their lives. 

Dr Shokat published in 2013, and that sharing of knowledge reinvigorated the hunt for KRAS binders. Dr. Greg Verdine, a Harvard scientist, was just then starting a company to find creative methods of binding proteins. He designed a strategy that combined Dr Shokat's results with a targeted molecular glue that made it possible to bind a drug to KRAS in its 'on state' and shut it down. Molecular glues are natural small molecules that can bring together two proteins that would not otherwise bind and are a very promising approach to molecular medicine. In this case, the small molecule is cyclophilin A, a ubiquitous protein that regulates protein folding and trafficking.

Dr. Verdine's company, Warp Drive Bio, merged with another company, Revolution, in 2018. Their combined efforts expanded the strategy and led to daraxonrasib, a drug that is designed to shut down KRAS in its 'on state'. 

The approach was novel, and the potential for devastating side effects loomed. KRAS is expressed throughout the body, not just in cancer cells, and so it seemed likely that disrupting such an important protein could lead to debilitating side effects. Shutting down 'on state' KRAS in mice had killed them. Amazingly, although there were side effects in a 2022 human safety study, they could be managed, and many of the patients' tumors were shrinking. Once again, a general assumption was overturned by new information. 

Mutated KRAS proteins fuel not just pancreatic cancers, but lung and colon cancers too making the need even greater. At this time, the drug is being fast-tracked by the FDA, and has been given the green-light for an early access program for patients with metastatic pancreatic cancer. The treatment is not a cure, not everyone responds, and the drug seems to eventually stop working. But to a patient fighting cancer, additional time is a miracle.

Scientific knowledge is continually expanding, updating, and sometimes even contradicting previous 'facts'.  More information can lead to an ever more accurate understanding of the world around us. As long as we are willing to challenge what we know, we have a chance to discover what we don't!

Photo by National Cancer Institute on Unsplash