Life in the RAS Lane: Frank McCormick and the Pursuit of Pancreatic Cancer’s Driver

From the quiet but dynamic English pond that captivated his childhood curiosity to the thrill of racing along California speedways, Frank McCormick, PhD, FAACR, has always appreciated motion and its mechanisms. But nothing has consumed his attention like his pursuit of the most infamous “driver” of cancer: RAS.

McCormick, who served as American Association for Cancer Research (AACR) President in 2012–2013, has spent the past four-plus decades deciphering the secrets of RAS and laying the foundation for new lanes of therapeutic possibilities. The progress he helped pioneer is especially significant for pancreatic cancer, a disease that remains difficult to treat and in which the vast majority of cases are driven by mutations in KRAS, one of three RAS genes in the human genome.

In recognition of his many extraordinary career contributions, the Stephenson Global Pancreatic Cancer Research Institute (SGPCRI) honored McCormick with the inaugural Stephenson Global Prize at the recent AACR Special Conference on Advances in Pancreatic Cancer Research: Emerging Science Driving Transformative Solutions. The Stephenson Global Prize is a $1 million prize that recognizes a lifetime of achievements that have significantly advanced pancreatic cancer research.

In a talk that was in equal parts career retrospective, scientific roadmap, and call to action, McCormick blended stories, humor, and hard-earned lessons to guide the audience through the discoveries that have reshaped our understanding of KRAS. After tracing its path from an enigma once thought undruggable to a protein that can now be targeted with growing success in multiple cancers, he also hinted at transformative breakthroughs on the horizon.

Noting that the support from the Stephenson Global Prize “will make a massive difference to my lab” and continuing research efforts, McCormick closed with the incredible possibility that these therapies might one day be able to prevent KRAS-driven cancers altogether.

“Astonished” by the Sensitive Oncogenic Scale

Some genes, like those in the RAS family, produce proteins that enable cells to proliferate. Under normal circumstances, they are tightly regulated to prevent excessive activity, but gene mutations and amplifications can transform their activity. And if KRAS gets stuck in its activated state, it triggers uncontrolled cell growth.

Opposing oncogenes and oncoproteins are tumor suppressors, which shut down cell growth signals, essentially acting as brakes. Typically, different oncogenic and tumor suppressor signals strike a necessary balance for specific biological contexts, allowing growth in appropriate circumstances. But if the gas pedal jams or the brakes fail, cells can progress toward malignancy.

Ironically, before diving into RAS, McCormick first made an impact through research into one of its main adversaries: the tumor suppressor protein p53. As a young researcher at the Imperial Cancer Research Institute in London, he developed the first antibodies that recognized p53, which is also frequently mutated in a range of cancers.

However, though p53 remains his second favorite protein, McCormick was soon lured to California at a very serendipitous time on the eve of “The Year of the Oncogene.” He was about to embark on what would become his lifelong race against RAS.

RAS has long been one of the most notorious oncogenes and has been implicated in nearly one in every five cancers, according to an analysis published in Cancer Research, a scientific journal of the AACR. The KRAS gene, in particular, contains more than 20,000 DNA base pairs that encode the more than 180 amino acids that make up the protein. If there’s a mistake in one of those 20,000 base pairs, it can send cells on the path toward cancer.

In 1982, McCormick remembers being “astonished by the fact that a single amino acid change in one protein in a cell can convert a normal cell into a wild-looking cancer cell.”

Soon thereafter, he would start adding his own seminal contributions to the story of RAS.

From “Party Tricks” to a Deeper Dive

In initially taking aim at the RAS pathway, McCormick showed that antibodies targeting mutant RAS could reverse transformation in cells. Though he downplayed this clever experiment as a “party trick” that did not yet offer a feasible therapeutic path, it crystallized the conviction that RAS could be targeted and set him off in search of small molecules more suited to the task.

After early attempts to drug RAS directly failed, McCormick turned his sights to RAS’s downstream pathway partners, such as RAF, which led to the development of sorafenib (Nexavar), a small molecule kinase inhibitor eventually approved by the FDA for kidney (in 2005), liver (in 2007), and thyroid cancers (in 2013). Despite its effectiveness in some cancer types, sorafenib blocks several other signaling pathways in addition to RAF and can trigger side effects. Most importantly, the therapy did not benefit patients whose cancers had mutated versions of KRAS, which McCormick admitted was “frustrating” because that “was the whole point of developing it in the first place.”

That frustration provided McCormick with fuel for further investigation: he desperately wanted to understand why previous efforts failed to disrupt mutant KRAS.

“You need to understand the biology of the system in depth to get the most out of therapies,” he explained. “The deeper the understanding, the better the chance of finding something that will work.” After becoming the founding director of the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center at the turn of the millennium, McCormick oversaw amazing research efforts that uncovered detailed insights into the biology of the RAS proteins, mapped the partners in the ensuing signaling cascades, and revealed why mutant KRAS stays stuck in its active state, among other discoveries.

This ethos, dedication, and expertise would result in McCormick being elected by the AACR membership to AACR President in 2012-2013, an opportunity that strengthened his decades-long relationship with Margaret Foti, PhD, MD (hc), the chief executive officer of AACR.

“Frank McCormick has a unique and extremely interesting approach to the conduct of science. Because he is very innovative, he excites everyone around him to try to reach their potential,” said Foti, who has always highly valued the leadership that he provided to AACR then and ever since.

“We have a Past President in him who continues to provide sage guidance to AACR, and we benefit greatly from his amazing intellect and his vision for the future of cancer research,” added Foti.

During his AACR presidency, McCormick refined his overarching framework for going after KRAS, which he unveiled at the AACR Annual Meeting 2013 in Washington, D.C. in his outgoing presidential speech, entitled “The End of KRAS Cancers?” Later that year, he put this thinking into practice with the launch of the National Cancer Institute-sponsored RAS Initiative at the Frederick National Laboratory for Cancer Research. He continues to serve as lead consultant on the initiative.

During his Stephenson Global Prize lecture, one dazzling slide was packed with eye-catching visualizations representing a small slice of the important discoveries. The illustration captured how far the field had advanced in terms of understanding KRAS at a precise, fundamental level.

Or, as McCormick joked, “This montage is just to give you the impression that we’ve done a lot of things involving heavy duty biophysics, computational sciences, structural biology, biochemistry screens.”

Clinical Breakthroughs and KRAS Treatments of Tomorrow

Four years ago, the long effort to crack mutant KRAS finally bore fruit, with the first approval of sotorasib (Lumakras), an inhibitor that targets a KRAS mutation called G12C. Adagrasib (Krazati) later received approval too, and now both treatments provide additional options for patients with KRAS G12C-mutated lung and colorectal cancers.

The development of these drugs rest on decades of the foundational KRAS biology that McCormick and his colleagues helped establish: structural studies, mechanistic insights, and a framework for how to approach KRAS as a drug target.

These approvals not only prove that mutant KRAS can be targeted effectively, but they also demonstrate the broad clinical relevance and immense potential impact that such inhibitors could have across cancers. Approvals of KRAS G12C inhibitors may be on the horizon for pancreatic cancer patients, but challenges remain for patients with other forms of RAS-mutated cancers.

Though current KRAS G12C inhibitors help some patients, researchers have identified potential resistance mechanisms that likely blunt responses and limit durability.

New KRAS G12C inhibitors, like the first-in-class BBO-8520 that McCormick discussed, target the KRAS G12C protein differently. In contrast to currently approved KRAS G12C inhibitors that bind mutant KRAS in its inactivated form, this experimental therapy currently being tested in a phase I trial is designed to target the activated form of KRAS. The discovery of BBO-8520 was first reported in Cancer Discovery, a high-impact scientific journal of the AACR.

More importantly, KRAS G12C mutations represent only a fraction of KRAS-driven cancers, and while common in lung cancer, they are relatively rare in pancreatic and colorectal cancers. Therefore, patients with KRAS G12D and KRAS G12V mutations are not covered by the currently approved drugs.

To that end, McCormick next shared data on BBO-11818, which expands its targeting reach beyond KRAS G12C. This treatment is known as a pan-RAS inhibitor because it can block the activity of KRAS G12C, G12D, and G12V, and the drug is currently in a phase I trial.

Reaching Beyond the Horizon: The Quest for Prevention

Beyond cancer, RAS biology also shapes inherited conditions such as neurofibromatosis type 1 (NF1), among others. In NF1, the loss of RAS regulation leads to the growth of benign tumors that can sometimes progress and become malignant. McCormick speculated that RAS-targeting therapies similar to those for cancer could be developed for these patients. And because these patients would likely require therapy across their entire lifespan, the need for drugs that are effective but also highly specific and safe becomes especially critical.

This broader perspective underscored a key point: Progress against RAS is about more than just new cancer drugs. It is about designing therapies precise enough to be used for both acute treatment and, eventually, lifelong management or even prevention of various diseases.

The Stephenson Global Prize was created to fuel exactly the kind of bold science that McCormick dares to attempt, and he ended his lecture with his boldest idea yet—not with the therapies of today, but with the possibilities of tomorrow.

As KRAS inhibitors grow more refined, McCormick envisions a future in which they could be used not only to treat, but also to prevent cancers in people at elevated risk. That vision could extend to older adults, whose risk of cancer climbs steadily with age; to NF1 patients, who almost invariably develop tumors due to dysregulated RAS signaling; and eventually to individuals determined to be at high risk due to features that can be detected early through advanced screening technologies.

“Frank McCormick is always thinking out of the box. We can make slow, incremental advances, but he consistently conceptualizes big, emerging areas, and I am excited to build upon our relationship, especially in the area of prevention, where there is a real buzz about its lifesaving potential,” said Foti, who expressed her confidence that the collaboration between AACR and SGPCRI “is going to be very fruitful in accelerating progress against pancreatic cancer.”

For McCormick, the vision is clear. His lifetime leadership in building RAS biology into a tractable field of drug discovery has been defined by chasing what once seemed impossible. Now, with the momentum from decades of discovery and support, McCormick remains determined to reach that elusive finish line and help end KRAS-driven cancers.