The approval of sotorasib (Lumakras) in 2021 to treat non-small cell lung cancer harboring the KRAS-G12C mutation transformed KRAS from an undruggable oncogene to a druggable therapeutic target and created an overnight sensation in cancer research and therapy. Targeting KRAS mutations directly set the stage for research into effective treatments for about a quarter of all human cancers, but the excitement obscured a more sobering reality. Sotorasib and subsequent KRAS-targeting agents are the result of decades of painstaking basic and applied cancer research.

Recent advances in immunotherapy and targeted therapy have significantly improved outcomes for many patients. However, these advances resulted in limited progress for those with RAS-mutated tumors, noted Dafna Bar-Sagi, PhD, Saul J. Farber Professor of Biochemistry and Molecular Pharmacology, Executive Vice President and Vice Dean for Science at NYU Langone Health. That scenario has changed dramatically with the emergence of therapeutics that target RAS directly and improvements in immune intervention technologies, she said.

Bar-Sagi will chair the first plenary session of the AACR Annual Meeting 2023, titled Beating KRAS: A 30-Year Overnight Sensation, from 4:15 – 6:15 p.m. ET Saturday, April 15, in W Hall A2-3 at the convention center. Plenary speakers will discuss the nearly 40-year history of KRAS — from its discovery in 1982 to the approval of sotorasib — and examine current strategies and the future of treating KRAS-mutated cancers.

“There are ongoing efforts to concomitantly block downstream pathways and pathways that are involved in immune suppression,” Bar-Sagi noted.

G12C is the most common mutation in RAS-driven tumors and is often seen in lung cancers. There are different RAS allele mutations in pancreatic and other cancers, which are the target of allele-specific inhibitors currently in development. One of the most exciting developments is pan-RAS inhibitors that are agnostic to the allele and target every constitutively active form of RAS, Bar-Sagi said.

In addition to small molecule inhibitors, researchers are striving to develop other therapies directed at KRAS-mutated tumors, such as adoptive cell therapies and vaccines against mutant forms of the protein.

These approaches represent a new personalized medicine strategy for many solid tumor indications, and having them work for RAS tumors would be a major advance in the field, Bar-Sagi said. She believes the tenacity and perseverance of researchers working in this space will bring this goal to fruition.

“The advances we have seen in recent years are the result of a lot of people working for many years, using multidisciplinary approaches with unwavering commitment,” Bar-Sagi said.

Anti-KRAS therapies hold promise for treating some of the deadliest cancers. However, we are learning that targeting RAS by itself will probably not be sufficient.

“We cannot afford quite yet to rest on our laurels,” said Bar-Sagi, noting that the next hurdle will be defining why and how tumors become resistant to these therapies and then designing novel approaches to overcoming resistance.