Loading
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.
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.
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.
It shows that the driver frequencies quoted in Western guidelines are population statistics rather than facts about the disease, which matters for how many patients anywhere are expected to benefit from a given medicine.
One pathway page on OnCo cites this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing page listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
It is the document that defines what a complete lung cancer molecular report looks like, and its asymmetry about plasma, rule in but never rule out, is the single most useful sentence in it.
It is the honest accounting of precision oncology in the disease where it works best: broad sequencing changes treatment for about one patient in three, and the bottleneck is evidence rather than detection.
It is the empirical basis for treating the two histologies as separate diseases for targeted therapy and as one disease for immunotherapy, which is exactly how they are treated.
It is the reference table the field still argues against, and it made two practical points that outlived it: a tumour with no driver on a standard panel usually has one that the panel did not look for, and pathway activity measured on protein does not follow from the mutation list.
It is the study that made multiplex testing standard practice in lung adenocarcinoma, by showing both that most tumours have a driver and that finding it changes what patients receive.
It explained why squamous lung cancer has no equivalent of an EGFR inhibitor: its commonest alterations are a transcription factor amplicon, a tumour suppressor deletion and an antioxidant switch, none of which is a drug target in the way a mutant kinase is.
Shares MEK1/2, The cell-cycle engine (cyclins & CDKs), AKT, Dabrafenib.
Shares Brigatinib, Pralsetinib, Lazertinib, Selpercatinib.
Shares Pralsetinib, MEK1/2, Selpercatinib, Dabrafenib.
Shares Distinct patterns of somatic genome alterations in lung adenocarcinomas and squamous cell carcinomas, Genomic landscape of lung adenocarcinoma in East Asians, Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies, Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer.
Shares MEK1/2, The cell-cycle engine (cyclins & CDKs), CDK4/6, p53 / RB / cell-cycle checkpoint.
Shares Pralsetinib, RET fusion-positive non-small-cell lung cancer, Lorlatinib, RET.
Shares Brigatinib, Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer, Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs, Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors.
Shares NTRK fusion-positive non-small-cell lung cancer, Selpercatinib, RET fusion-positive non-small-cell lung cancer, ROS1-positive non-small-cell lung cancer.