Adaptive mutability of colorectal cancers in response to targeted drug therapy

Mutagenesis (process that enhances the number of DNA mutations) can drive carcinogenesis (initiation of cancer formation) and continue during cancer progression — generating intra-tumor genetic heterogeneity that enables cancer cells to adapt, via Darwinian evolution. Analyses (e.g. mutational signature characterization) have revealed specific mutational processes and their temporal activity during carcinogenesis and tumor progression. Nevertheless, many of the mechanisms that promote genomic instability in cancer are still puzzling. Authors [see attached article & editorial] show anti-cancer drugs that target tumor-causing epidermal growth factor receptor (EGFR) or BRAF (A gene that encodes B-RAF protein, which is involved in signaling pathways that enhance cell growth) signaling increase mutagenesis in colorectal cancer (CRC) cells — which can lead to the development of chemotherapy resistance to various anti-cancer drugs. Hence, the GEITP connection to gene-environment interactions (anti-cancer drug is the environmental signal; genes in the tumor cell respond to this signal by mutating, hoping these changes allow the tumor to survive). Just like an evolutionary process.

Authors [see attached article & editorial] discovered that human colorectal cancer (CRC) cell lines — following treatment with EGFR or BRAF inhibitors — down-regulated expression of high-fidelity DNA repair proteins and increased expression of error-prone DNA repair proteins, both of which lead to increases in mutation rates. Using reporter assays, authors further showed that the fidelity of DNA mismatch repair (MMR) and homologous recombination (HR) repair systems were impaired, and that DNA damage increased during drug treatment.

Genetic analysis of cell lines that had been exposed to these inhibitors revealed subclonal mutations in dinucleotide repeats, which are characteristic of defective MMR. In contrast to other cancer mutational processes — such as genetically encoded HR or

MMR defects that lead to persistent mutation acquisition or overexpression of apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) DNA cytidine deaminases, which generates mutational bursts — the mutagenesis program identified by these authors was tightly coupled to drug exposure; moreover, the mutagenesis program ceased after drug removal. This study demonstrates that nongenotoxic targeted oncogene pathway inhibitors can promote a temporally restricted increase in mutability by switching from high-fidelity to error-prone DNA repair.

In conclusion, EGFR/BRAF inhibition down-regulates MMR and HR DNA-repair genes and, at the same time, up-regulates error-prone polymerases in drug-tolerant (persister) cells. MMR proteins were also down-regulated in patient-derived xenografts (patient’s cancer tissue transplanted into mice) and tumor specimens during anti-cancer therapy. EGFR/BRAF inhibition resulted in increased DNA damage, mutability, and microsatellite instability. Thus, just like bacteria and other single-celled organisms, tumor cells evade therapeutic pressures (i.e. environmental signals that threaten their survival) by enhancing mutability (in the hopes that these new mutations will help the tumor survive). This is one mechanism for drug resistance developing in a patient who is undergoing anti-cancer therapy. Adaptation to adverse changes in the environment is also what drives evolution. 😊


Science 20 Dec 2019; 366: 1473-1480 & editorial pp 1452-1453

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