# KRAS roadmap: undruggable → G12C → pan-RAS

Source: https://onco.cc/roadmaps/kras-roadmap/  
OnCo record `kras-roadmap` (Roadmap). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

The most important cancer gene was declared undruggable for 40 years. Then a pocket was found, and now a pan-RAS drug is in phase 3 for pancreatic cancer.

## Summary

The KRAS roadmap begins with the gene's discovery as a human oncogene and decades of failure, when farnesyltransferase inhibitors did not work, until the Shokat lab found the switch-II pocket and sotorasib and adagrasib were approved in NSCLC. The current step goes beyond G12C with non-covalent G12D inhibitors and pan-RAS(ON) tri-complex inhibitors such as daraxonrasib in pancreatic cancer, and the emerging step anticipates a first pancreatic approval, combinations, KRAS vaccines, mutant-KRAS TCR-T and RAS degraders. The speculative end is neoadjuvant RAS inhibition and interception in high-risk cyst carriers. KRAS drives the three common cancers with the lowest survival; the route links pancreatic, colorectal and NSCLC, the KRAS target, KRAS and RAS inhibitors and the undruggable-drivers bottleneck.

## Fields

- Kind: Roadmap
- Last checked: 2026-09-04

## Sources

- Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable (Nature 2013): https://doi.org/10.1038/nature12796
- CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer (New England Journal of Medicine 2023): https://doi.org/10.1056/NEJMoa2308795

## Connected records

- roadmaps: [Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation](https://onco.cc/roadmaps/colorectal-roadmap/), [Lung cancer roadmap: from Doll and Hill and the naming of tobacco, through the cytotoxic plateau, computed tomography screening, EGFR and ALK, immunotherapy by PD-L1, the perioperative trials and PACIFIC, to DLL3 in small-cell disease and a 2032 registry watch](https://onco.cc/roadmaps/lung-cancer-evidence-roadmap/), [Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question](https://onco.cc/roadmaps/pancreatic-roadmap/), [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [KRAS G12C-mutant pancreatic ductal adenocarcinoma](https://onco.cc/cancers/kras-g12c-pdac/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Non-small-cell lung cancer](https://onco.cc/cancers/nsclc/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- fronts: [Targeted Therapy](https://onco.cc/fronts/targeted-therapy/)
- technologies: [KRAS & RAS inhibitors](https://onco.cc/technologies/kras-inhibitors/), [Multi-cancer early detection (MCED)](https://onco.cc/technologies/mced/), [Off-the-shelf cancer vaccines](https://onco.cc/technologies/shared-antigen-vaccine/), [TCR-T cell therapy](https://onco.cc/technologies/tcr-t/)
- targets: [KRAS](https://onco.cc/targets/kras/)
- drugs: [Adagrasib](https://onco.cc/drugs/adagrasib/), [Daraxonrasib](https://onco.cc/drugs/daraxonrasib/), [Sotorasib](https://onco.cc/drugs/sotorasib/)
- pairings: [KRAS G12C inhibitor + anti-EGFR antibody (colorectal)](https://onco.cc/pairings/kras-plus-egfr-crc/)
- companies: [Revolution Medicines](https://onco.cc/companies/revolution-medicines/)
- key papers: [CodeBreaK 200: sotorasib versus docetaxel in KRAS G12C-mutated lung cancer, a modest win for the first KRAS drug](https://onco.cc/key-papers/paper-codebreak-200-lancet-2023/), [CodeBreaK 300: sotorasib plus panitumumab in chemotherapy-refractory KRAS G12C colorectal cancer](https://onco.cc/key-papers/paper-codebreak-300-nejm-2023/), [Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy](https://onco.cc/key-papers/paper-holderfield-ras-on-multi-selective-inhibitor-nature-2024/), [Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes](https://onco.cc/key-papers/paper-almoguera-kras-codon-12-pancreatic-cell-1988/), [Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable](https://onco.cc/key-papers/paper-ostrem-kras-g12c-nature-2013/)
- ideas: [An open-science consortium on the undruggable drivers, open until a candidate](https://onco.cc/ideas/idea-fund-precompetitive-undruggable-consortium/), [RAS inhibitor combinations and sequence: pan-RAS plus G12D-selective, plus chemotherapy, and what to give after progression](https://onco.cc/ideas/idea-pdac-ras-inhibitor-combinations-and-sequencing/)
- bottlenecks: [The undruggable drivers](https://onco.cc/bottlenecks/b-undruggable-targets/)

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JSON: https://onco.cc/api/v1/entities/kras-roadmap.json