Adaptive Mutability May Underlie Some Resistance to Targeted Therapies

The prevailing view of the mechanism behind resistance to targeted anticancer therapies is that resistant subclones are already present prior to treatment initiation and begin to predominate once treatment eliminates nonresistant cells. However, Russo and colleagues found that another mechanism may also be involved in resistance. Their experiments indicate that, like bacteria exposed to antibiotics, colorectal cancer cells transiently increase their mutation rate in response to exposure to targeted therapies (EGFR or BRAF inhibitors), a phenomenon termed adaptive mutability. In vitro experiments showed that treatment with targeted therapies decreased mismatch-repair (MMR) and homologous-recombination proficiency in colorectal-cancer cells and caused increased dependence on error-prone DNA repair. Experiments using patient-derived tumor samples produced matching results, with samples from colorectal-cancer residual disease exhibiting downregulation of MMR proteins. Markers of DNA damage were elevated in colorectal-cancer cells treated with targeted therapies; concomitantly, levels of reactive oxygen species were increased, providing hints about a possible mechanism behind the DNA damage. Further experiments implied that treatment with targeted therapies did not simply have nonspecific effects that resulted in DNA damage, but rather that the treatments triggered initiation of a stress-response program, resulting in adaptive mutability and genetic instability. Notably, the changes in DNA repair in cancer cells associated with treatment with targeted therapies was temporary, reverting to normal once growth capability in the presence of the therapies was acquired, just as in microbial adaptive mutability. These findings not only indicate that a shift in thinking about how resistance occurs may be needed, but also provide a conceptual basis for the development of therapies that interfere with adaptive mutability to improve targeted therapies' efficacy.

Russo M, Crisafulli G, Sogari A, Reilly NM, Arena S, Lamba S, et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science 2019 Nov 7 [Epub ahead of print].

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