Command Palette

Search for a command to run...

Preprint WatchModerateOctober 1st, 2026

Hyper-mutational processes provide a head-start for weak cancer drivers: explaining atypical KRAS variants

Nicholson, M. D.; Tomlinson, I.

Elevated mutation rate and context-specific mutational bias alone, without altered selection, are sufficient to explain the enrichment of atypical weak-driver KRAS variants in hypermutant cancers.

Moderate contradiction

2 prior failures

Two documented clinical failures match this mechanism, or a single Phase 3 failure is on record.

This modelling paper argues that atypical KRAS driver variants become prevalent in hypermutant cancers through mutation rate and sequence-context bias rather than through any selective advantage, meaning a frequently observed variant need not be a strong oncogenic driver. That distinction bears directly on target selection for the two KRAS programmes recorded in the Claidex graph, BGB-53038 (bgb-53038-kras-solid-tumors-phase1-strategic-reprioritization) and the sotorasib plus durvalumab study (sotorasib-durvalumab-kras-g12c-ctdna-stage3-nsclc-phase2-enrollment-collapse), because both selected patients on variant presence. If prevalence in a hypermutant background reflects mutational process rather than driver strength, then recruiting on variant detection alone can enrich for tumours whose growth does not actually depend on KRAS. The flag is MODERATE because the work is computational and the claim is about which patients a variant-directed trial will capture, not about whether the drug engages its target.

Abstract excerpt

Hypermutant cancers frequently contain atypical driver gene variants, which may provide sub-optimal oncogenic advantages. The reason why weak cancer drivers prevail and are not outcompeted by stronger alternatives is unclear. Here, using mathematical modelling, we show that aberrant mutational processes alone can account for the detection of weak, rather than canonical, driver mutations. We find that simply increasing the mutation rate per cell division, without altering selection or mutational biases, can lead to the dominance of weak drivers due to rapidly occurring further driver events. This effect can be further enhanced by mutational biases towards specific nucleotide sequence contexts. Focusing on POLE-mutant (DNA polymerase epsilon proofreading-deficient) colorectal cancers, we quantify the mutation bias for varied KRAS drivers under both POLE-mutant and non-hypermutant mutational processes. In POLE-mutant cancers, the combination of the bias coupled with an elevated mutation rate is sufficient to explain the enrichment of atypical KRAS drivers. Furthermore, model predictions are consistent with the observed prevalence of atypical KRAS drivers observed in mismatch repair deficient colorectal cancer. Thus, differential selection across these cancer types need not be invoked to explain the variation in driver mutations. Our study clarifies the interplay of mutation and selection during the evolutionary dynamics of tumourigenesis.

Matching Claidex post-mortems

2 of 2 indexed

This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.