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bioRxiv · 10.64898/2026.10.12.758643

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.
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Abstract

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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V, M., Koladiya, A., Thennavan, A., Yu, X., Lozano, G.. 2026-10-14. Trp53 heterozygosity defines novel states impacting tumor plasticity and progression in Kras-initiated non-small cell lung cancer. https://doi.org/10.64898/2026.10.12.758643

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