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The RAS-MAPK pathway is the cell's 'divide' relay. A signal at the surface flips RAS on, which passes to RAF, MEK, and ERK, which tell the nucleus to make the cell divide. KRAS and BRAF mutations jam it in the on position.
Growth-factor receptors recruit GRB2/SOS to load GTP onto RAS (KRAS, NRAS, HRAS). RAS-GTP recruits RAF (BRAF, CRAF) dimers, which phosphorylate MEK1/2, which phosphorylate ERK1/2. ERK drives transcription of cyclin D1, MYC, and negative feedback (DUSP, SPRY). Alterations: KRAS (pancreatic 90%, CRC 45%, lung 30%), BRAF V600E (melanoma 50%), NF1 loss, receptor fusions (ALK, RET, NTRK). Drugs: KRAS G12C inhibitors, pan-RAS(ON) inhibitors, BRAF+MEK doublets, upstream RTK inhibitors. Feedback reactivation (loss of ERK-mediated inhibition of RTKs) is why single agents fail and vertical combinations (BRAF+MEK, KRAS+EGFR in CRC) work.
A relay race: receptor hands the baton to RAS, RAS to RAF, RAF to MEK, MEK to ERK, ERK runs into the nucleus and shouts 'divide'. A KRAS mutation is a runner who never stops running whether or not anyone handed them the baton.
One of the most cited trial reports Europe PMC returns for Daraxonrasib in Pancreatic ductal adenocarcinoma, so it is a natural first reading for anyone weighing the idea it is linked from. The record was linked automatically by title and abstract; read the abstract above and the paper itself before relying on any figure.
Patients with newly diagnosed metastatic colorectal cancer whose tumour carries a BRAF V600E mutation, which is about 8-12% of cases, should now be offered encorafenib and cetuximab together with FOLFOX from the start rather than after chemotherapy fails; median survival has roughly doubled to about two and a half years. BRAF testing at diagnosis is therefore essential, alongside RAS and mismatch repair testing. The regimen is more toxic than chemotherapy alone.
The mechanism that let one drug address G12D, G12V and G12R together, which is why the RASolute 302 trial could enrol unselected pancreatic cancer and nearly double survival.
Sotorasib is a guideline-listed later-line option for the 1 to 2 percent of pancreatic cancers with KRAS G12C, and the proof that KRAS in pancreatic cancer is druggable; the larger opportunity lies with inhibitors of G12D and pan-RAS drugs.
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.
Adagrasib plus cetuximab is an approved option for previously treated KRAS G12C colorectal cancer, alongside sotorasib plus panitumumab; monotherapy is not enough because EGFR signalling reactivates the pathway.
This is the fusion and immune-marker table for the wild-type minority, the group in which RNA sequencing pays for itself.
Shares Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma, Phosphorylation, GRB7, Salmonella Typhi carriage and gallbladder cancer.
Shares KRAS G12C inhibitor + anti-EGFR antibody (colorectal), KRAS G12C metastatic colorectal cancer: specific features of a new emerging target population, Quanta Therapeutics, KRYSTAL-1: adagrasib with or without cetuximab in KRAS G12C-mutated colorectal cancer.
Shares Macrocyclic peptides to cover protein surfaces that pills cannot, Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia, Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets, Signalling pathway.
Shares Salmonella manipulation of host signaling pathways provokes cellular transformation associated with gallbladder carcinoma, Salmonella Typhi carriage and gallbladder cancer, Milestone prizes for first-in-class mechanisms reaching human proof of concept, Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma.
Shares Milestone prizes for first-in-class mechanisms reaching human proof of concept, Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma, An open-science consortium on the undruggable drivers, open until a candidate, MicroRNAs in cancer.
Shares Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes, CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer, Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets, Association of alterations in main driver genes with outcomes of patients with resected pancreatic ductal adenocarcinoma.
Shares K-ras mutations and benefit from cetuximab in advanced colorectal cancer, BRF113928 cohort C (dabrafenib with trametinib, untreated BRAF V600E), Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas, Rosai-Dorfman-Destombes disease.
Shares KRAS G12C inhibitor + anti-EGFR antibody (colorectal), Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes, Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy, An open-science consortium on the undruggable drivers, open until a candidate.