Targeted cancer therapy induces APOBEC fuelling the evolution of drug resistance

Abstract

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.

Cancer evolution: Darwin and beyond

“…Therefore, therapeutic strategies targeting the mechanisms responsible for drug tolerance may prevent, or at least delay, the evolution of acquired resistance (Fig 3 ). This strategy was tested in a recent study where the selective pressure exerted by EGFR inhibitors in lung cancer was shown to induce APOBEC3B overexpression, leading to increased cancer cell mutability, fostering tumour adaptation to treatment (preprint: Mayekar et al , 2020 ). Similar findings were reported in colon cancer, whereby drug‐tolerant cells were shown to temporarily down‐regulate mismatch repair (MMR) and homologous recombination DNA repair genes in favour of error‐prone polymerases as an adaptive response to overcome BRAF and EGFR inhibition (Russo et al , 2019 ).…”

DNA replication during acute MEK inhibition drives acquisition of resistance through amplification of theBRAFoncogene

“…We would therefore hesitate to label genome instability caused by under-expression of replication proteins as a mutagenic response, though our study provides strong support for the suggestion that non-genotoxic drug treatment can increase mutation rate and drive the emergence of resistance. Whether mutagenesis is intentional or not, our study and others addressing drug-induced mutation (28,58) provide grounds for optimism that resistance to targeted chemotherapeutics is preventable, since mutational mechanisms that act during chemotherapy can be characterised and suppressed.…”

The APOBEC3B cytidine deaminase is an adenovirus restriction factor

“…Indeed, upregulation of A3B has been observed in many tumors types and has been demonstrated to contribute to the A3 mutational signature [30][31][32]. Moreover, A3B expression in tumor has been shown to fuel genetic diversity of the tumor cells, favoring metastasis and drug resistance [33][34][35]. Finally, one of the limitations of oncolytic viruses' efficacy, is the expression by the host cells of the A3B protein [36].…”