RAS / RAF / MEK / ERK (MAPK)
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.
In one picture
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.
Diagram
top- KRAS G12C inhibitors (sotorasib, adagrasib) ± anti-EGFR in colorectal cancer
- Pan-RAS(ON) inhibitor daraxonrasib (phase 3, pancreatic)
- BRAF + MEK inhibitors (dabrafenib/trametinib, encorafenib/binimetinib)
- Encorafenib + cetuximab (+ chemo) in BRAF V600E CRC
- Upstream: EGFR, ALK, RET, MET, NTRK inhibitors and bispecifics