# Drivers, passengers & the two-hit model

Source: https://onco.cc/pathways/oncogene-activation-two-hit/  
OnCo record `oncogene-activation-two-hit` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Summary

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).

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- Analogy: 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.
- Interventions: 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Knudson_hypothesis
- Vogelstein et al., Cancer genome landscapes (Science 2013): https://doi.org/10.1126/science.1235122
- Kinzler & Vogelstein, Gatekeepers and caretakers (Nature 1997): https://doi.org/10.1038/386761a0

## Connected records

- cancers: [Chronic myeloid leukaemia (CML)](https://onco.cc/cancers/cml/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Multiple endocrine neoplasia syndromes (MEN1, MEN2, MEN4)](https://onco.cc/cancers/multiple-endocrine-neoplasia/), [Retinoblastoma](https://onco.cc/cancers/retinoblastoma/)
- technologies: [Comprehensive genomic profiling](https://onco.cc/technologies/cgp/), [CRISPR functional genomics](https://onco.cc/technologies/crispr-screens/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Synthetic lethality approaches](https://onco.cc/technologies/synthetic-lethality-approaches/)
- targets: [ALK](https://onco.cc/targets/alk/), [BCR::ABL1 (Philadelphia chromosome)](https://onco.cc/targets/bcr-abl/), [BRAF](https://onco.cc/targets/braf/), [BRCA1 / BRCA2 (HRD)](https://onco.cc/targets/brca/), [EGFR](https://onco.cc/targets/egfr/), [EWSR1-FLI1 fusion](https://onco.cc/targets/ewsr1-fli1/), [HER2](https://onco.cc/targets/her2/), [KRAS](https://onco.cc/targets/kras/), [NF1 (neurofibromin)](https://onco.cc/targets/nf1/), [PRMT5 (MTAP-deleted cancers)](https://onco.cc/targets/prmt5-mtap/), [TP53](https://onco.cc/targets/tp53/)
- drugs: [Imatinib](https://onco.cc/drugs/imatinib/), [Olaparib](https://onco.cc/drugs/olaparib/), [Osimertinib](https://onco.cc/drugs/osimertinib/), [Sotorasib](https://onco.cc/drugs/sotorasib/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/)
- pathways: [Clonal evolution & minimal residual disease](https://onco.cc/pathways/clonal-evolution/), [Mutagenesis & mutational signatures](https://onco.cc/pathways/mutagenesis-signatures/), [p53 / RB / cell-cycle checkpoint](https://onco.cc/pathways/p53-cell-cycle/), [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/), [Theories of cancer: how the ideas connect](https://onco.cc/pathways/theories-of-cancer/)
- terms: [Driver and passenger mutations: the refined somatic mutation theory](https://onco.cc/terms/driver-passenger-model/), [Gene fusion](https://onco.cc/terms/gene-fusion/), [Germline vs somatic mutations](https://onco.cc/terms/germline-vs-somatic/), [Hereditary cancer syndromes](https://onco.cc/terms/hereditary-cancer-syndromes/), [Oncogene addiction](https://onco.cc/terms/oncogene-addiction/), [Somatic mutation theory of cancer](https://onco.cc/terms/somatic-mutation-theory/), [Synthetic lethality](https://onco.cc/terms/synthetic-lethality/), [Variant of uncertain significance (VUS)](https://onco.cc/terms/vus/)
- key papers: [Cancer-susceptibility genes. Gatekeepers and caretakers](https://onco.cc/key-papers/paper-kinzler-nature/)

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