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Preprint WatchModerateOctober 15th, 2026

Trp53 heterozygosity defines novel states impacting tumor plasticity and progression in Kras-initiated non-small cell lung cancer

V, M.; Koladiya, A.; Thennavan, A.; Yu, X.; Lozano, G.

Single-allele Trp53 loss defines tumour states distinct from complete TP53 loss in Kras-initiated non-small cell lung cancer, with longer survival and altered tumour plasticity, implying that TP53 allelic status is a modifier of KRAS-driven disease rather than a binary covariate.

Moderate contradiction

2 prior failures

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

The claim here is that TP53 allelic dosage, not merely TP53 status, shapes tumour plasticity and progression in KRAS-initiated lung cancer. That matters for how KRAS trials are stratified. Claidex records two KRAS programmes that stopped without answering their efficacy question: bgb-53038-kras-solid-tumors-phase1-strategic-reprioritization was deprioritised at Phase 1, and sotorasib-durvalumab-kras-g12c-ctdna-stage3-nsclc-phase2-enrollment-collapse closed on accrual with a ctDNA-based selection strategy that took no account of TP53 allelic state. If heterozygous and complete TP53 loss define different disease biology, pooling them dilutes any KRAS-directed effect, and the preprint supplies a concrete prespecifiable covariate that neither prior trial used.

Abstract excerpt

KRAS and TP53 are frequently mutated in non-small cell lung cancer (NSCLC), the leading cause of cancer-related mortality worldwide. The most common event at the TP53 locus is mutation/loss of one allele and retention of a wild-type allele, which confers better survival outcomes than complete TP53 loss. To study the contribution of TP53 heterozygosity, we generated a murine lung tumor model with a KrasG12D mutation and intact (K) or single-allele loss (KP+/-) of Trp53 and compared it with publicly available complete loss (KP) data. K and KP+/- mice lived longer than KP mice, paralleling clinical survival data. Single-cell transcriptomic analysis of tumor-burdened lungs indicated that Trp53 heterozygosity expanded transcriptional plasticity that was not present in K and KP tumors. Genomic instability was also higher in KP+/- mice relative to the KP genotype. Trp53 gene dosage, thus, regulates phenotypic plasticity and evolutionary trajectories of tumor states across K, KP+/-, and KP tumors. Murine KP+/- tumor signatures and copy-number profiles were present in human NSCLC datasets. Two of these signatures correlated with better and worse patient survival outcomes, respectively. TP53 heterozygosity in KRAS-mutant lung cancers presents a distinct genomic landscape that should be taken into account in the development of novel therapeutic strategies.

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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.