Progress against RAS-driven cancers lauded at RAS Symposium, with more candidate treatments on the horizon

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Researchers from around the world met in October to mark progress their field has made in developing drugs to treat cancers driven by the RAS oncogene, and to map out even more ways they can help cancer patients. 

“This is a great story about tackling an intractable disease that was said to be an impossible task,” said National Cancer Institute Director W. Kimryn Rathmell, M.D., who welcomed participants to the fifth, three-day RAS Symposium. “That challenge motivated people to take it on. It’s a paradigm for success and a program that should be replicated.” 

The RAS Symposium brings together basic and clinical RAS investigators every two years to evaluate and share their approaches to attack proteins encoded by mutant forms of RAS genes and to ultimately create effective, new therapies for RAS-driven cancers.  

Many of the participants collaborate as part of the NCI’s RAS Initiative, for which FNL is the research hub, with a focus on mutant (oncogenic) KRAS due to its prevalence in pancreatic, lung, and colorectal cancers. 

RAS complexity has been a barrier to progress 

Although researchers discovered oncogenic RAS in the 1960s, it took decades for scientists to find a pocket on the gene, to which they could potentially attach a small-molecule drug that would turn encoded proteins off to slow or stop the cancer. That 2013 discovery, in the laboratory of Kevan Shokat, Ph.D. at the University of California San Francisco, showed the KRAS G12C mutation could be targeted with a small molecule. It reinvigorated the field. 

The pace of RAS discoveries has quickened over the last decade, with multiple therapies in clinical trials and new approaches under pre-clinical evaluation in laboratories. The first treatment for KRAS-driven non-small cell lung cancer became available to patients in 2021.  

Margaret Foti, Ph.D., M.D. (hc), CEO of the American Association for Cancer Research, called it a “transformational era in cancer research, with greater translation of basic science to the clinic,” that will extend to the other KRAS-driven cancer types, including pancreatic and colorectal cancers. 

“We’ve come a long way from when we only had 5fu and Adriamycin,” Foti told symposium attendees, referring to legacy chemotherapy drugs to treat colorectal cancer. “We have to be spirited in what we can accomplish.” 

Beyond monotherapy: Combination treatments critical to impact pancreatic cancers, KRAS drug resistance 

KRAS mutations drive most pancreatic cancers, and pancreatic cancer is the deadliest of all major cancer types. As basic scientists and clinicians develop and test a growing number of KRAS drugs, there is an urgency to specifically target pancreatic cancer. 

One promising approach is to combine KRAS inhibitors with other types of cancer treatments, including chemotherapy, immunotherapy, and PARP inhibitors.  

Presenters cited preclinical models of pancreatic cancer treated with an EGFR inhibitor and a KRAS inhibitor that showed tumor regression, as did another model treated with three drugs.  

Symposium speakers, including FNL and NCI investigators, academic researchers, and scientists representing companies with compounds in clinical trials, agreed that combining KRAS drugs with other types of cancer treatments could address one of the greatest challenges facing KRAS drug development – resistance.  

Most patients whose tumors respond to KRAS G12C therapy eventually develop resistance to it. The drug stops working and cancer growth resumes.   

Using a combination of treatments may hold off resistance that occurs when the patient is being treated exclusively with a KRAS G12C drug. On the other hand, presenters agreed, the combination therapy may induce resistance of its own. The field is working to better understand mechanisms of primary and acquired resistance, and combination treatments are being tested in clinical trials to learn more. 

New approaches to target KRAS  

Frank McCormick, Ph.D., scientific director of the RAS Initiative, said he is proud to be part of the FNL team behind a KRAS G12C drug now in human clinical trials, and two others with different mechanisms of action to treat RAS-related cancers. 

KRAS drives cancer via multiple pathways that relay signals from outside a cell to its nucleus. McCormick said FNL’s Dhirendra Simanshu, Ph.D. solved the structure of the RAS interaction with PI3Kα kinase, a RAS effector, which facilitates signaling. This paved the way for FNL and partners BridgeBio Oncology Therapeutics (BBOT) and the Lawrence Livermore National Laboratory (LLNL) to discover and develop a “breaker” drug candidate that blocks the interaction. The candidate will be in clinical trials before the end of the year, he said. 

McCormick, an investigator at the University of California San Francisco who has led the RAS Initiative since its inception, said the third drug candidate is a “pan-KRAS” compound, which targets multiple KRAS mutations in addition to KRAS G12C, and has the potential to benefit a wider range of cancer patients. The pan-KRAS candidate was developed by the RAS Initiative, BBOT, and LLNL collaborators.