Alexander Drilon, MD: KRAS has long been known to be "undruggable" for a variety of factors. The KRAS protein itself was perceived to lack a good drug binding pocket outside of the nucleotide binding pocket of the RAS molecule. In addition, RAS does complex itself with GTP, or bind to GTP. In fact, it has a very high affinity for GTP, making it difficult for us to design GTP-competitive inhibitors, to outcompete the GTP molecule for that particular pocket. We've tried many different strategies in the past, and to name a few of them, there have been farnesyl transferase inhibitors that inhibit the localization of RAS to the membrane; those didn't work. We tried to leverage the fact that RAS activates downstream pathways, such as the MEK and ERK pathways, and have given either single-agent MEK or ERK inhibitors or combinations that hit these downstream pathways. While we've seen isolated responses in patients here and there, we haven't really seen a single series result in a very large number of patients who benefit from therapy.
Jonathan Riess, MD, MS: KRAS G12C direct inhibitors have been an exciting development and potentially a transformational development in the treatment of non–small cell lung cancer. Several years ago, Kevan Shokat’s, PhD, laboratory and his colleagues identified small molecules that can irreversibly bind to the mutant reactive cysteine at residue 12. They identified a previously unappreciated binding pocket near the KRAS effector region. Small molecules binding to this pocket can inhibit KRAS by locking the protein in a GDP balance in inactive state. That development has spurred these new small molecule, direct KRAS G12C inhibitors that preliminarily looked to be able to induce responses and to be efficacious, particularly in non–small cell lung cancer. That's been an exciting development, that we're now able to take these small molecules to the clinic and see responses.
In terms of the rationale for identifying that cysteine at residue 12, it can target the binding pocket near the KRAS effector region where it locks the protein and its GDP bound in an active state. That underlies its activity as a direct KRAS inhibitor. I think once again that's an exciting development to be able to target that binding pocket.
It shouldn't affect wild-type KRAS in that situation because the G12C substitutes a glycine for a cysteine. Potentially, EGFR inhibition may have some impact on wild-type KRAS, and that interaction may potentiate activity. That's being studied in future clinical trials.
In terms of tethering approach to drug design, that's a methodology to screen ligands that bind to targeted site proteins via a disulfide tether, where a native cysteine or an introduced cysteine can capture the ligands. That's a way to screen for these direct KRAS inhibitors of G12C. It's the drug development approach that was initially taken to identify these small molecule inhibitors of KRAS G12C.
Paul Bunn, MD: For KRAS, there are some covalent drugs that have been developed. These drugs covalently bind to the receptor and prevent GTP binding activation. These G12C agents that bind covalently are called AMG 510 and MRTX849. These are the first KRAS-specific drugs that have entered a clinical trial. Early clinical trial results have established safety, dose, and some efficacy of both of these agents. There's a limited number of patients, less than 30 for both drugs, so we don't actually have anywhere near enough data to have these drugs approved yet. We don't know the median progression-free survival, the overall survival, what it will be with these drugs. But we do know that these drugs can cause responses in 50% or more of KRAS G12C mutations.
Transcript Edited for Clarity