KRAS mutations were a shining example of undruggable cancer targets for decades following their discovery in the early 1980s. The KRAS-G12C inhibitors sotorasib and adagrasib broke a 40-year drought in targeted treatment, but G12C mutations account for only about 20 percent of all KRAS-mutant solid tumors.

“G12C is only the third most common mutation of KRAS,” said Kevan M. Shokat, PhD, FAACR, professor of cellular and molecular pharmacology at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center. “G12C is very prevalent in lung tumors, but less so in colon and very minimal in pancreatic cancers. Other mutations, G12D in particular, are dominant and much harder to target than G12C. But there have been significant advances in the last three years.”

Shokat will chair the session KRAS: Broadening the Attack Beyond G12C with Small Molecules and Immuno-Oncology on Tuesday from 12:30 – 2 p.m. PT in Ballroom 20 AB on the upper level of the San Diego Convention Center. G12D is the most common KRAS mutation in pancreatic ductal adenocarcinoma as well as colorectal, non-small cell lung, and other cancers. His lab developed the first G12C inhibitor in 2013 and recently published a candidate G12D inhibitor.

Shokat and Elena S. Koltun, PhD, vice president of medicinal chemistry at Revolution Medicines, will discuss the latest findings in KRAS chemistry and structure in the continuing search for novel small molecules that target G12D mutations.

The problem in treating KRAS-mutant tumors, he continued, is that KRAS is an elusive target for small molecules. KRAS-mutant tumors routinely develop resistance, more often sooner than later.

“Everybody recognizes that small molecules alone, especially in solid tumors, don’t give us the cure,” Shokat said. “In order to improve response and get to a potential cure, we need to bring in the immune system.”

Sandra B. Gabelli¸ PhD, currently executive director of discovery chemistry and head of protein and structural chemistry at Merck, will discuss the latest advances in focusing the immune system on KRAS mutations including her work while a professor at Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center. The biologics approach retargets the immune system that is not fully engaged with the tumor. The combination of small-molecule targeted therapy plus a more fully energized immune system focused on tumor cell surface proteins unique to G12D mutations should be more effective than either approach as a monotherapy.

“We don’t know for sure; we have had only a few trials in G12D with the new targeting,” Shokat said. “But there is good logic behind merging the two approaches. Cross resistance to both attacks would require multiple resistance mechanisms to develop simultaneously, which is always more difficult for a tumor than developing consecutive mechanisms to sequential agents.”

The hope, he added, is that progress to date will help spark new approaches to target G12D as well as the second most-common KRAS variant, G12V. Between them, G12 D, V, and C account for about 80 percent of all KRAS-mutant solid tumors.

“These three talks are very chemical, very molecular, with a lot of crystal and cryo-EM [cryo-electron microscopy] structures,” Shokat said. “These kinds of presentations let people see how things fit together. Maybe they can trigger some new approaches that the three of us haven’t thought of.”