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The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies.

Original publication

DOI

10.1038/s41467-024-47606-9

Type

Journal article

Journal

Nature communications

Publication Date

06/2024

Volume

15

Addresses

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.

Keywords

TRACERx consortium, Cell Line, Tumor, Animals, Humans, Mice, Lung Neoplasms, Chromosomal Instability, Protein Kinase Inhibitors, Drug Resistance, Neoplasm, Mutation, Female, Male, Tumor Suppressor Protein p53, DNA Copy Number Variations, Molecular Targeted Therapy, ErbB Receptors, Adenocarcinoma of Lung