Mixed responses to targeted therapy driven by chromosomal instability through p53 dysfunction and genome doubling

• Published in: Nature communications Vol. 15; no. 1; pp. 4871 - 21
• Main Authors: Hobor, Sebastijan, Al Bakir, Maise, Hiley, Crispin T, Skrzypski, Marcin, Frankell, Alexander M, Bakker, Bjorn, Watkins, Thomas B K, Markovets, Aleksandra, Dry, Jonathan R, Brown, Andrew P, van der Aart, Jasper, van den Bos, Hilda, Spierings, Diana, Oukrif, Dahmane, Novelli, Marco, Chakrabarti, Turja, Rabinowitz, Adam H, Ait Hassou, Laila, Litière, Saskia, Kerr, D Lucas, Tan, Lisa, Kelly, Gavin, Moore, David A, Renshaw, Matthew J, Venkatesan, Subramanian, Hill, William, Huebner, Ariana, Martínez-Ruiz, Carlos, Black, James R M, Wu, Wei, Angelova, Mihaela, McGranahan, Nicholas, Downward, Julian, Chmielecki, Juliann, Barrett, Carl, Litchfield, Kevin, Chew, Su Kit, Blakely, Collin M, de Bruin, Elza C, Foijer, Floris, Vousden, Karen H, Bivona, Trever G, Hynds, Robert E, Kanu, Nnennaya, Zaccaria, Simone, Grönroos, Eva, Swanton, Charles
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 13.06.2024; Nature Publishing Group UK; Nature Portfolio
• Subjects: Adenocarcinoma; Adenocarcinoma of Lung - drug therapy; Adenocarcinoma of Lung - genetics; Adenocarcinoma of Lung - pathology; Animal models; Animals; Cancer therapies; Cell Line, Tumor; Chromosomal Instability; Copy number; DNA Copy Number Variations; Drug resistance; Drug Resistance, Neoplasm - genetics; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Female; Genomes; Genomic instability; Humans; Kinases; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Male; Metastases; Mice; Molecular Targeted Therapy - methods; Mutation; p53 Protein; Patients; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Stability; Therapy; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Tyrosine; Tyrosine kinase inhibitors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47606-9

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.