Russo et al. found that human CRC cell lines that
were treated with EGFR or BRAF inhibitors down-regulated the expression
of high-fidelity DNA repair proteins and increased that of error-prone
DNA repair proteins, which may both increase mutation rates. Using
reporter assays, they 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 the APOBEC
(apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like) DNA
cytidine deaminases, which generates mutational bursts—the mutagenesis program identified by Russo et al.
was tightly coupled to drug exposure and 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. Adaptive mutagenesis is a mechanism described in bacteria that increases the mutation rate in response to cell stress.
This is triggered by a cell-stress signaling pathway that activates
error-prone DNA double-strand break repair and it is accompanied by
suppression of MMR. Adaptive mutagenesis increases the probability of
generating mutations that enable evolutionary adaptation of unicellular
organisms to new environments. On the basis of the pronounced
similarities of drug-induced mutagenesis in CRC and adaptive mutagenesis
in bacteria, Russo et al. explored whether the mammalian
target of rapamycin (mTOR) pathway, a major stress signaling pathway in
humans, controls drug-induced mutagenesis in cancer cells. mTOR
signaling was indeed inactivated by drug treatment, but inhibiting the
mTOR pathway alone did not phenocopy the changes in DNA repair protein
expression. The trigger of drug-induced mutagenesis in CRC cells is
therefore either more complex or different from that in bacteria.
This is not at all unexpected. Indeed this is a clear suggestion that any single genetic control can and is adaptively bypassed. Initial control may be effected but it will be essential to treat many cancers as chronic diseases as they move from genetic change to genetic change.
The challenge going forward will be to detect and address these changes in some dynamic basis. One suspects that non-invasive liquid biopsies may be effective.
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