Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2.

on behalf of the CCGA Consortium. Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31(6):745e759. 2. Taylor WC. Comment on 'Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA' by M. C. Liu et al.

Introductory paragraphThe clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients1-4. Human tumours can evolve therapy resistance by acquiring de novo genetic alterations and increased heterogeneity via mechanisms that remain incompletely understood1. Here, through parallel analysis of human clinical samples, tumour xenograft and cell line models and murine model systems, we uncover an unanticipated mechanism of therapy-induced adaptation that fuels the evolution of drug resistance. Targeted therapy directed against EGFR and ALK oncoproteins in lung cancer induced adaptations favoring apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC)-mediated genome mutagenesis. In human oncogenic EGFR-driven and ALK-driven lung cancers and preclinical models, EGFR or ALK inhibitor treatment induced the expression and DNA mutagenic activity of APOBEC3B via therapy-mediated activation of NF-κB signaling. Moreover, targeted therapy also mediated downregulation of certain DNA repair enzymes such as UNG2, which normally counteracts APOBEC-catalyzed DNA deamination events. In mutant EGFR-driven lung cancer mouse models, APOBEC3B was detrimental to tumour initiation and yet advantageous to tumour progression during EGFR targeted therapy, consistent with TRACERx data demonstrating subclonal enrichment of APOBEC-mediated mutagenesis. This study reveals how cancers adapt and drive genetic diversity in response to targeted therapy and identifies APOBEC deaminases as future targets for eliciting more durable clinical benefit to targeted cancer therapy.

Novel targeted drugs, mainly in oncology, have commanded substantial price premiums in the recent past. Consequently, the attention of pharmaceutical companies has shifted away from the traditional low-price and high-volume blockbuster business model to drugs that command high, and sometimes extremely high, prices in limited markets defined by targeted patient populations. This model may have already passed its zenith, as the impact of more and more high-priced drugs coming to market substantially increases their combined burden on payors and public health finances. This article introduces a new 'balanced value' business model for personalized medicine, leveraging the emerging opportunities to reduce drug development cost and time for targeted therapies. This model allows pharmaceutical companies to charge prices for targeted therapy below the likely future thresholds for payors' willingness to pay, at the same time preserving attractive margins for the drug developers.