Adaptive mutability of colorectal cancers in response to targeted therapies

Abstract

The emergence of drug resistance limits the efficacy of targeted therapies in human tumors. The prevalent view is that resistance is a fait accompli: when treatment is initiated, cancers already contain drug-resistant mutant cells. Bacteria exposed to antibiotics transiently increase their mutation rates (adaptive mutability), thus improving the likelihood of survival. We investigated whether human colorectal cancer (CRC) cells likewise exploit adaptive mutability to evade therapeutic pressure. We found that epidermal growth factor receptor (EGFR)/BRAF inhibition down-regulates mismatch repair (MMR) and homologous recombination DNA-repair genes and concomitantly up-regulates error-prone polymerases in drug-tolerant (persister) cells. MMR proteins were also down-regulated in patient-derived xenografts and tumor specimens during therapy. EGFR/BRAF inhibition induced DNA damage, increased mutability, and triggered microsatellite instability. Thus, like unicellular organisms, tumor cells evade therapeutic pressures by enhancing mutability.

From single gene analysis to single cell profiling: a new era for precision medicine

“…By using a liquid biopsy approach that allows the detection of emerging resistant cancer clones before relapses are clinically manifest, they discovered that a multistep clonal evolution of drug resistant cells underlies the development of resistance to anti-EGFR antibodies in cells and CRC patients. Intriguingly, this supports the general concept that CRC cells likewise exploit adaptive mutability to evade therapeutic pressure [42]. She further reported that the generation of new mutations is accelerated when genes involved in DNA repair pathways are altered and that the manipulation of the mutational burden can trigger persistent therapeutic responses.…”

Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance

“…Interestingly, therapeutic stresses such as EGFR/BRAF inhibitors decrease the levels of MMR and HR DNA repair genes, meanwhile increase the errorprone polymerases. These actions prompt adaptive DNA mutability and ultimately restrain chemotherapy efficacy by conferring cancer cell resistance [85].…”

Drug Resistance in Non-Hodgkin Lymphomas

“…Besides the generally accepted fact that tumor heterogeneity itself inevitably results in acquired drug-resistance, because it can be viewed as a reservoir of preexisting drug-resistant clones, single tumor cell plasticity can lead to adaptive transcriptional and post-transcriptional changes that can result in the derivation of the so-called "drug-tolerant persister" (DTP) cells ( Figure 1A) [53]. It has been demonstrated that DTP cells exposed to anti-tumor drugs exploit adaptive mutability (a process similar to the increased mutation rate of bacteria exposed to antibiotics), which is achieved through the down-regulation of mismatch repair and homologous recombination genes with concomitant overexpression of error-prone polymerases [54]. In contrast to preexisting drug-resistant mutant clones, the drug-tolerant phenotype of DTP cells can be dynamically acquired and relinquished [55].…”