Quest.

Last Thursday, February 9, Kevan M. Shokat, Ph.D., Reed Class of 1986, received the Vollum Award for Distinguished Accomplishment in Science and Technology at an event held in Vollum Lecture Hall, hosted by President Bilger and introduced by Biology Professor Janis Shamplay. This was the first Vollum Award ceremony held since 2018. According to a pamphlet handed out before the event, the Vollum Award was created in 1975 to honor the late Reed alum and trustee C. Howard Vollum. The award is “intended to recognize and celebrate the exceptional achievement of a member of the scientific and technical community of the Pacific Northwest.” Dr. Shokat, as the newest award recipient, will be in the company of Bill Gates and Steve Jobs, the latter being a famously brief Reed student. Dr. Shokat himself is now a professor of cellular and molecular pharmacology at the University of California, San Francisco, and a professor of chemistry at the University of California, Berkeley, as well as an investigator at the Howard Hughes Medical Institute. 

Following the award presentation, Dr. Shokat gave an in-depth lecture on the research he and his lab team have been doing for the better part of a decade, and the pioneering medical breakthroughs they’ve accomplished in the process. This work has been published not only in medical journals, but also in a recent New York Times article which details all that they have discovered. Dr. Shokat began his talk by explaining why cancer is such a difficult disease to treat, primarily arguing that finding drugs that affect only cancer cells can be incredibly challenging. He explained that the body has mechanisms to stop cancer cell proliferation, specifically the TP53 gene, a type of tumor suppressor gene that can halt cancer cell replication. However, the TP53 gene can often mutate itself and lose its tumor suppressor function, allowing tumor growth to continue. While Dr. Shokat did speak briefly about potential drugs that may be able to “rescue” the TP53 suppressor function, he revealed that his lab’s research was primarily dedicated to blocking the function of the KRAS gene, from which the G12C mutation causes more than 1 in 10 lung cancers worldwide, as well as many colorectal and pancreatic cancers. The goal of Dr. Shokat and his lab was to discover a drug-compatible molecule that could block KRAS function, which would significantly challenge a tumor’s ability to grow.

Dr. Shokat’s work was built off of decades of research targeting KRAS mutations. Starting in 1983 there was an effort to block KRAS membrane localization, which proved initially promising but ultimately failed, and was shut down in the late 1990s. Dr Shokat’s team, after years of searching, found a molecule that could form an irreversible covalent bond with the amino acid cysteine, which occurs only in mutated KRAS genes. Dr. Shokat expressed elation at this discovery, as the uniqueness of cysteine’s presence in the mutated KRAS gene allowed for exactly the kind of specifically targeted drug cancer researchers look for: a drug that will only affect cancer cell function, without causing other harmful side effects. Two drugs were initially approved, sotorasib in 2021 and adagrasib in 2022. Based on a graph of preliminary clinical results for the drugs, approximately 80% of lung cancer patients saw some amount of tumor shrinkage after taking the medication, but Dr. Shokat insists that there is considerable room for improvement. There are now more than ten cysteine-binding drugs on the market or in clinical trials today. 

After the discovery of a cysteine binder, Dr. Shokat’s team moved on to look for molecules that would bind to other amino acids found in mutated KRAS genes, such as serine and arginine, which are both significantly harder to affect due to their less reactive chemical structures compared to cysteine. It took his team ten more years to find a serine binder. Dr. Shokat stressed that if drugs could be created that would bind to all of the amino acids found in mutated KRAS genes, treatments could become exponentially more effective, not just in treating lung cancer, but other KRAS affected cancers like colon and pancreatic, the latter of which being particularly lethal. Finally, Dr. Shokat floated the prospect of finding a drug that could restore TP53 tumor suppressor function, allowing the body itself to gain the upper hand against cancer cell proliferation. A combination of all these drugs could prove a groundbreakingly potent attack against tumor growth, and research is not only ongoing, but incredibly promising.

By Henry Kendrick