Article
作者: Grönroos, Eva ; McGranahan, Nicholas ; Frankell, Alexander M ; Markovets, Aleksandra ; Venkatesan, Subramanian ; Al Bakir, Maise ; Litière, Saskia ; Black, James R M ; Novelli, Marco ; Foijer, Floris ; Hobor, Sebastijan ; Kelly, Gavin ; Wu, Wei ; Rabinowitz, Adam H ; Blakely, Collin M ; Hiley, Crispin T ; Chew, Su Kit ; Hynds, Robert E ; Renshaw, Matthew J ; Bivona, Trever G ; Vousden, Karen H ; Ait Hassou, Laila ; Dry, Jonathan R ; Moore, David A ; van den Bos, Hilda ; Huebner, Ariana ; Bakker, Bjorn ; Downward, Julian ; van der Aart, Jasper ; Tan, Lisa ; Skrzypski, Marcin ; Watkins, Thomas B K ; Kanu, Nnennaya ; Oukrif, Dahmane ; Swanton, Charles ; Zaccaria, Simone ; Martínez-Ruiz, Carlos ; Hill, William ; Angelova, Mihaela ; Kerr, D Lucas ; Chakrabarti, Turja ; Spierings, Diana ; Litchfield, Kevin ; Barrett, Carl ; Chmielecki, Juliann ; de Bruin, Elza C ; Brown, Andrew P
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.