MTOR signaling orchestrates stress-induced mutagenesis, facilitating adaptive evolution in cancer

Abstract

In microorganisms, evolutionarily conserved mechanisms facilitate adaptation to harsh conditions through stress-induced mutagenesis (SIM). Analogous processes may underpin progression and therapeutic failure in human cancer. We describe SIM in multiple in vitro and in vivo models of human cancers under nongenotoxic drug selection, paradoxically enhancing adaptation at a competing intrinsic fitness cost. A genome-wide approach identified the mechanistic target of rapamycin (MTOR) as a stress-sensing rheostat mediating SIM across multiple cancer types and conditions. These observations are consistent with a two-phase model for drug resistance, in which an initially rapid expansion of genetic diversity is counterbalanced by an intrinsic fitness penalty, subsequently normalizing to complete adaptation under the new conditions. This model suggests synthetic lethal strategies to minimize resistance to anticancer therapy.

Receptor-Driven ERK Pulses Reconfigure MAPK Signaling and Enable Persistence of Drug-Adapted BRAF-Mutant Melanoma Cells

“…However, viable cell number remains approximately constant because the number of newly born cells balances the number of dying cells. We find that, under these conditions, dividing cells experience replication stress and express the error-prone polymerases previously proposed to facilitate emergence of clones carrying resistance mutations (Russo et al, 2019;Cipponi et al, 2020). Thus, continued survival and division of persister cells may promote genetically encoded resistance in melanoma, but direct measurement of mutation frequency will be required to test this hypothesis.…”

“…In patients, therapeutic responses to combined RAF and MEK inhibition therapy are often rapid and dramatic, but in most cases they are also transitory due to the emergence of drug-resistant clones (Groenendijk and Bernards, 2014). Emerging evidence suggests that rapid adaptation to targeted drugs by non-genetic mechanisms promotes sustained survival of persister cells, contributes to residual disease, and facilitates emergence of resistance mutations responsible for disease recurrence in patients (Pazarentzos and Bivona, 2015;Russo et al, 2019;Cipponi et al, 2020). However, the molecular mech-anisms underlying drug adaptation, the emergence of persister cells, and selection for drug-resistant clones are only partially understood.…”

Intrinsic growth heterogeneity of mouse leukemia cells underlies differential susceptibility to a growth-inhibiting anticancer drug

“…It is of note that generation times of the slow-cycling leukemia cells characterized in this study were less than 40 h in most cases; thus, they should still be referred to as proliferative rather than quiescent cells. It is an intriguing question whether the slow-cycling phenotype is a prerequisite for the acquisition of stronger drug resistance, possibly mediated by drastic changes in metabolic states or triggering adaptive mutations [39,40]. solution (10 µl/well) was added to the wells.…”

Gene Panel of Persister Cells as a Prognostic Indicator for Tumor Repopulation After Radiation

“…Activation of MTOR signaling was shown to confer multiple cancer types with resistance to chemo-radiation (42,43). An elegant work recently using whole-genome RNAi screening identified MTOR as a common orchestrator in stress-induced genomic instability, accelerating the adaptation of cancers in cytotoxic condition and facilitating the cancer resistance to different oncotherapy (44). Moreover, the combination of 5-FU and temsirolimus, an mTOR inhibitor, reduced the chemoresistance related persister cells in gastric cancer (8).…”