Non-small cell lung cancer (KEGG map)
KEGG's non-small cell lung cancer map shows a set of alternative on-switches (EGFR mutation, KRAS mutation, EML4-ALK, RET and MET alterations) that all feed the same RAS/ERK, PI3K/AKT and STAT relays, plus loss of the p16 and p53 brakes. Each on-switch now has its own targeted pill, which is why molecular testing comes before treatment.
Overview
The KEGG non-small cell lung cancer map (hsa05223) is a map of mutually exclusive oncogenic drivers. Activating EGFR mutations (exon 19 deletions and L858R) or EGFR overexpression signal through GRB2/SOS to KRAS, through PLC-gamma and PKC to ERK, and through PI3K to AKT. KRAS point mutations (G12C among them) disable GTP hydrolysis so the protein continuously transmits growth signals to RAF, MEK and ERK. The EML4-ALK fusion, created by an inversion on chromosome 2p, gives constitutive ALK kinase activity feeding PLC-gamma to ERK, PI3K to AKT and JAK to STAT3/STAT5. RET fusions and MET mutations or amplification are further drivers feeding RAS to ERK and PI3K, and ERBB2 overexpression adds to the receptor input. On the suppressor side, loss of p16INK4a (CDKN2A) frees CDK4/6 and cyclin D to phosphorylate RB, TP53 mutation removes apoptosis and arrest, RASSF1A loss shifts RAS output toward growth, and RAR-beta silencing removes retinoid growth control. Herbst, Morgensztern and Boshoff, Nature, 2018 (doi:10.1038/nature25183) review how this driver map, together with PD-L1 expression and tumour mutational burden, now dictates first-line treatment, and how resistance emerges through on-target mutations (EGFR T790M, C797S; ALK G1202R), bypass through MET amplification, and histological transformation to small cell carcinoma.
What drugs do about it: EGFR mutations are treated with osimertinib (alone or with chemotherapy) or amivantamab with lazertinib, and exon 20 insertions with amivantamab or sunvozertinib; KRAS G12C with sotorasib, adagrasib and the newer divarasib and olomorasib; ALK fusions with alectinib, brigatinib or lorlatinib; RET fusions with selpercatinib or pralsetinib; MET exon 14 skipping with capmatinib, tepotinib or savolitinib, and MET overexpression with telisotuzumab vedotin; BRAF V600E with dabrafenib plus trametinib; HER2 mutations with trastuzumab deruxtecan or zongertinib; and driver-negative tumours with pembrolizumab or other PD-1/PD-L1 antibodies, with or without chemotherapy.
In one picture
A room full of light switches wired to the same bulb. In each patient's tumour just one switch is jammed on (EGFR, KRAS, ALK, RET or MET), so the first job is to find which one, then fit a cover that matches that switch. If no switch is jammed, the immune system is unleashed on the bulb instead.
Diagram
top- EGFR-mutant disease: osimertinib (alone or with chemotherapy), amivantamab plus lazertinib; amivantamab or sunvozertinib for exon 20 insertions
- KRAS G12C: sotorasib, adagrasib, divarasib, olomorasib
- ALK fusions: alectinib, brigatinib, lorlatinib; RET fusions: selpercatinib, pralsetinib; MET exon 14 or overexpression: savolitinib, telisotuzumab vedotin
- BRAF V600E: dabrafenib plus trametinib; HER2 mutations: trastuzumab deruxtecan, zongertinib
- Driver-negative tumours: pembrolizumab or other PD-1/PD-L1 antibodies with or without platinum chemotherapy
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