Introductory paragraph The clinical success of targeted cancer therapy is limited by drug resistance that renders cancers lethal in patients 1-4 . Human tumours can evolve therapy resistance by acquiring de novo genetic alterations and increased heterogeneity via mechanisms that remain incompletely understood 1 . 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.

Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance