Drivers, passengers & the two-hit model
Of the thousands of mutations in a tumour, only a handful (typically 2-8) actually drive it. Drivers either jam an accelerator on (oncogenes, one hit is enough) or remove a brake (tumour suppressors, both copies must go). Everything else is a passenger along for the ride.
Vogelstein's landscape: ~140 driver genes, each tumour carrying 2-8 driver events in ~12 pathways, on a background of tens to thousands of passengers. Oncogene activation is dominant and recurrent at hotspots: point mutation (KRAS G12, BRAF V600E, PIK3CA H1047R), amplification (HER2, MYC, MDM2), fusion (BCR-ABL, ALK, RET, NTRK, EWSR1-FLI1), promoter mutation (TERT) or ecDNA. Tumour suppressor loss follows Knudson's two hits, one inherited in hereditary syndromes (RB1, BRCA1/2, APC, MLH1, TP53), the second by deletion, LOH, mutation or methylation; some are haploinsufficient (PTEN). Gatekeepers (APC, RB1) control proliferation directly; caretakers (BRCA, MMR) guard the genome so their loss accelerates all other hits. Oncogene addiction, the dependence of a tumour on its driver, is why kinase inhibitors work; passenger load creates neoantigens and, occasionally, collateral vulnerabilities (MTAP deletion next to CDKN2A → PRMT5 dependence).
In one picture
A car with a stuck accelerator (oncogene: one fault is enough) and cut brake lines (tumour suppressor: both lines must fail because they are duplicated). The scratches on the paintwork (passengers) did not cause the crash but they tell you what road it drove on.
Diagram
top- Oncogene addiction is the basis of every targeted kinase inhibitor and of HER2 antibodies
- Suppressor loss cannot be 'inhibited', so it is exploited indirectly: synthetic lethality (BRCA-PARP, MTAP-PRMT5), CDK4/6 for RB-intact, MDM2 for TP53-wild-type
- Germline first hits drive surveillance and risk-reducing surgery in hereditary syndromes
- Comprehensive genomic profiling separates drivers from passengers at diagnosis
Pages like this
not linked directly; found by shared links- PathwaySynthetic lethality: paired dependencies
Shares PRMT5 (MTAP-deleted cancers), Synthetic lethality, Oncogene addiction, Synthetic lethality approaches and the tags mechanism, mechanics-atlas.
- PathwayDouble-strand break repair: HR versus end joining
Shares Hereditary cancer syndromes, Mutagenesis & mutational signatures, Synthetic lethality, Germline vs somatic mutations and the tags mechanism, mechanics-atlas.
- PathwayResistance routes: how a blocked pathway comes back
Shares BCR::ABL1 (Philadelphia chromosome), Sotorasib, Clonal evolution & minimal residual disease, ALK and the tags mechanism, mechanics-atlas.
- PathwayReceptor tyrosine kinase activation
Shares Oncogene addiction, Gene fusion, ALK, Imatinib and the tags mechanism, mechanics-atlas.
- PathwayThe p53 network (guardian of the genome)
Shares Germline vs somatic mutations, Synthetic lethality approaches, p53 / RB / cell-cycle checkpoint, Germline (hereditary) testing and the tags mechanism, mechanics-atlas.
- PathwayDrug-tolerant persister cells
Shares Clonal evolution & minimal residual disease, BRAF, Osimertinib, KRAS and the tags mechanism, mechanics-atlas.
- PathwayMismatch repair & microsatellite instability
Shares Mutagenesis & mutational signatures, Synthetic lethality approaches, Germline (hereditary) testing, Comprehensive genomic profiling and the tags mechanism, mechanics-atlas.
- PathwayThe blood–brain barrier & brain metastasis
Shares ALK, Osimertinib, HER2, EGFR and the tags mechanism, mechanics-atlas.