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Using disulfide-tethering screens, Shokat's laboratory found small molecules that bind covalently to the mutant cysteine of KRAS G12C in a previously unknown pocket beneath switch II, locking the oncoprotein in its inactive GDP-bound state.
KRAS had been considered undruggable for three decades because it binds GTP with picomolar affinity and has no obvious deep pocket. Ostrem and colleagues exploited the cysteine introduced by the G12C mutation, present in about 13% of lung adenocarcinomas, screening a library of cysteine-reactive fragments by tethering.
Crystal structures revealed that the hits bound in a cryptic pocket (switch-II pocket, S-IIP) that exists only in the GDP-bound state. The compounds impaired SOS-catalysed nucleotide exchange, shifted KRAS towards GDP binding, and reduced Raf effector binding, selectively killing G12C-mutant cells. The compounds were weak but demonstrated mechanism.
This work led directly to ARS-853, ARS-1620 and then sotorasib (approved 2021) and adagrasib (2022), the first KRAS inhibitors, and inspired covalent and non-covalent approaches to other RAS mutants.
The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets.
Patients with KRAS G12C lung cancer that has progressed after chemo-immunotherapy can take an oral KRAS inhibitor instead of docetaxel and gain a somewhat longer time to progression with fewer severe side effects, but should understand that most tumours become resistant within a year and that survival is not improved. KRAS G12C testing is worthwhile, but first-generation inhibitors are a step rather than a cure; combinations and next-generation inhibitors are the active research fronts.
Patients with metastatic colorectal cancer carrying a KRAS G12C mutation (about 3-4% of cases) who have exhausted standard chemotherapy now have a targeted option that works far better than trifluridine-tipiracil or regorafenib. The higher sotorasib dose is clearly superior, and the EGFR antibody is essential because KRAS inhibition alone has little effect in bowel cancer. Responses are still modest and short-lived compared with EGFR or ALK inhibitors in lung cancer.
The reason pancreatic cancer is the proving ground for RAS drugs: nearly every tumour depends on the same mutant protein, so a drug that works against it works for nearly every patient.
Shares KRAS roadmap: undruggable → G12C → pan-RAS, Daraxonrasib, Nature, KRAS & RAS inhibitors.
Shares Ferdinandos Skoulidis, CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug, Sotorasib, KRAS G12C-mutant non-small-cell lung cancer.
Shares Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes, UCSF Helen Diller Family Comprehensive Cancer Center, KRAS G12C-mutant pancreatic ductal adenocarcinoma, KRAS & RAS inhibitors.
Shares KRAS roadmap: undruggable → G12C → pan-RAS, Adagrasib, Sotorasib, KRAS & RAS inhibitors.
Shares Daraxonrasib, KRAS & RAS inhibitors, The undruggable drivers, RAS / RAF / MEK / ERK (MAPK).
Shares KRAS G12C-mutant pancreatic ductal adenocarcinoma, KRAS & RAS inhibitors, The undruggable drivers, Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question.
Shares CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug, Daraxonrasib, KRAS G12C-mutant pancreatic ductal adenocarcinoma, Sotorasib.
Shares Daraxonrasib, KRAS G12C-mutant pancreatic ductal adenocarcinoma, KRAS G12C-mutant non-small-cell lung cancer, KRAS & RAS inhibitors.