Cancer therapy has entered the era of precision medicine, where treatments are guided by the genetic mutations found in a patient’s tumor. But not all mutations behave as expected, and not every patient responds the way clinical guidelines predict.
Tommy McFall, PhD, Assistant Professor of Biochemistry, is working to understand these inconsistencies. His research focuses on how specific mutations influence cell signaling and treatment response, uncovering therapeutic opportunities that traditional models have missed.
A central focus of his work is KRAS, one of the most commonly mutated genes in cancer. KRAS mutations have long been considered “undruggable,” with few effective therapies and limited clinical options. By challenging long-held assumptions about how certain KRAS mutations function, the McFall Lab is uncovering new ways to treat some of the most aggressive and difficult-to-treat cancers.
“Some of the biggest opportunities in cancer research come from rethinking what we thought we knew. My work focuses on the mutations and mechanisms we’ve overlooked, the ones that might hold the key to better treatments,” said Dr. McFall.
Cracking the Code on KRAS Mutations
As a postdoctoral fellow at the Salk Institute for Biological Studies, Dr. McFall set out to solve a longstanding mystery in colorectal cancer. Patients with mutations in the KRAS gene are typically not given EGFR inhibitors like cetuximab because these mutations are thought to make drugs ineffective. But some patients with a specific variant, KRAS G13D, were still responding.
Using computational modeling and lab experiments, Dr. McFall discovered that KRAS G13D interacts only weakly with a tumor suppressor protein called neurofibromin (NF1). Because of this weak interaction, it doesn’t fully shut down the activation of normal, or wild-type, RAS through EGFR signaling. That leaves a window of opportunity where EGFR inhibitors can still be effective.
“These unexpected responses had puzzled researchers for years,” said Dr. McFall. “But we found that the way a mutation behaves—how it interacts with proteins like NF1—can be just as important as the mutation itself.”
He went on to identify 10 more RAS mutations with similar properties, potentially expanding EGFR inhibitor eligibility to an estimated 24,000 patients in the U.S. each year who would otherwise be overlooked.
Turning Discovery Into Clinical Progress
To help move these insights from lab to clinic, Dr. McFall worked with the MCW Cancer Center Translational Council (TC), a team of leaders across scientific disciplines that help researchers connect with collaborators, access resources, and translate promising discoveries into real-world solutions.
With guidance from the Council, collaboration with clinical researchers from the Discovery and Developmental Therapeutics Program, and a Cancer Center pilot award, Dr. McFall built upon his findings to secure his first R01 grant and launch two investigator-initiated clinical trials—MCW I-PREDICT, led by Dr. Ben George, and a study evaluating MEK inhibitor-based treatments for KRAS G12R-mutated advanced pancreatic cancer, led by Dr. Mandana Kamgar.
“Collaboration is key in advancing cancer research, and the TC not only connected me with the right people but also helped refine my approach. Now, these discoveries are being translated into clinical trials that could make a real difference for patients,” said Dr. McFall.
A New Path Forward in Precision Oncology
Currently, Dr. McFall’s work is focused on KRAS G12R, a mutation found in about 20% of pancreatic ductal adenocarcinoma (PDAC) cases. Pancreatic cancer remains one of the deadliest cancers, with limited targeted therapy options and a five-year survival rate below 12%.
His lab discovered that KRAS G12R has weaker interactions with two important signaling proteins, NF1 and SOS1. This leads to reduced activation of the RAS pathway, which plays a key role in cell growth. Because the pathway is already weakened, tumors with this mutation are more likely to respond to MEK inhibitors, especially when combined with autophagy inhibitors like hydroxychloroquine, which further block the tumor’s ability to survive.
“G12R hadn’t been studied as much as other KRAS mutations,” said Dr. McFall. “We found it behaves differently at the molecular level, and that difference may open the door to new treatments.”
These findings helped launch a small clinical study. Of eight patients with KRAS G12R-mutated pancreatic cancer, five had progression-free survival of at least six months. One patient saw their tumor shrink by 83% and stayed stable for nearly nine months.
Rather than seeing responses like this as rare exceptions, Dr. McFall treats them as valuable clues. His team is now exploring how this approach can be applied to other tumor types and whether diagnostic tools can better identify patients with this kind of mutation profile. “If we understand why something works for one patient, we might figure out how to make it work for many more,” he said.