MTOR was a critical node modulating stress-induced mutagenesis (SIM) in cancer in vitro and in vivo.
Major Finding: MTOR was a critical node modulating stress-induced mutagenesis (SIM) in cancer in vitro and in vivo.
Concept: In cancer, the role of SIM—increased mutation rate in response to selective pressure—has been murky.
Impact: This supports SIM's relevance in cancer and suggests drug combinations to exploit this vulnerability.
An increased mutation rate resulting from an organism's maladaptation to its environment, termed stress-induced mutagenesis (SIM), has been observed in prokaryotes and some lower eukaryotes. It has been suggested that SIM could be a way that some cancer cells respond to the selective pressure induced by treatments, but little is known about how this may occur. Using paired pre- and post-treatment samples from patients with diverse cancers as well as patient-derived pancreatic cancer xenografts, Cipponi and colleagues found evidence of DNA damage (as evidenced by DNA double-strand breaks) following treatment with nongenotoxic drugs, providing evidence for SIM in this context. Further work in human cancer cell lines also supported this conclusion, demonstrating that there was increased genetic diversity following treatment with targeted therapies that was paired with a fitness penalty early in the adaptation process. A whole-genome RNAi screen to identify the mediators of SIM in human cancer pinpointed MTOR—known to be involved in the DNA-damage response—as a critical node controlling the SIM response in cancer cells. MTOR inhibition or silencing promoted adaptive mutagenesis by preventing accurate DNA repair via transcriptional repression of genes encoding proteins in the homologous recombination and Fanconi anemia pathways as well as genes encoding high-fidelity (but not error-prone) DNA polymerases. Together, these results support a model in which strong selective pressure exerted by treatment means MTOR-mediated SIM confers a survival advantage to some cells, despite the overall fitness penalty of increased mutational load. Once resistant clones have been established, the SIM response is normalized and the new, resistant genomic configurations are fixed. This model suggests that combination treatment with cytostatic chemotherapy plus a genotoxic drug may be effective, and, supporting this notion, a proof-of-concept experiment in a patient-derived pancreatic cancer xenograft model showed that combination treatment with the CDK4/6 inhibitor palbociclib and the PARP inhibitor rucaparib had a synergistic antitumor effect. In summary, this work provides further evidence for SIM in human cancer along with potentially actionable mechanistic insight into the process.
Cipponi A, Goode DL, Justin Bedo J, McCabe MJ, Pajic M, Croucher DR, et al. MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer. Science 2020;368:1127–31.
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