Mutagenesis can drive carcinogenesis and continue during cancer progression, generating genetic intratumor heterogeneity that enables cancer adaptation through Darwinian evolution (1). Analyses, such as mutational signature characterization, have revealed specific mutational processes and their temporal activity during carcinogenesis and tumor progression (2). Nevertheless, many of the mechanisms that promote genomic instability in cancer are still enigmatic. On page 1473 of this issue, Russo et al. (3) reveal that drugs targeting oncogenic epidermal growth factor receptor (EGFR) or BRAF signaling increase mutagenesis in colorectal cancer (CRC) cells, which could drive the acquisition of resistance.

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 (4)—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 (5). 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.

Russo et al. speculate that it may nevertheless be the same ancestral stress-induced mutagenesis program found in unicellular organisms that becomes unleashed in cancer. Whether this program could have survived millions of years of evolution from unicellular to multicellular species is unclear. Stress-induced mutagenesis is risky in multicellular organisms because it may trigger cancer in healthy cells, thereby threatening the survival of the individual. Somatic mutagenesis is clearly relevant in humans, for example, in B lymphocytes, in which it contributes to antibody diversity generation. However, this somatic hypermutation program is tightly restricted to immunoglobulin genes, whereas inactivation of high-fidelity DNA repair confers a genome-wide mutator process that can alter oncogenes and tumor suppressor genes. An alternative hypothesis is that the observed changes in DNA repair protein expression in response to signaling pathway inhibition fulfill a physiological function in healthy cells but aggravate mutation generation in cancer cells that have deregulated proliferation and apoptosis. Drug-induced mutagenesis may be a by-product that coincidentally opens opportunities for cancer cells under selective pressure, rather than having specifically evolved as a program that enables cellular adaptation to stress.


Models of acquired drug resistance

Models of resistance mechanisms to epidermal growth factor receptor (EGFR) inhibitors in colorectal cancer include preexisting resistance, drug-induced mutagenesis, and microenvironment-mediated resistance. Each reveals distinct therapeutic opportunities, but multiple mechanisms may occur within a tumor.




The results of Russo et al. are important because resistance invariably occurs in CRCs after patients are treated for a few months with EGFR or BRAF inhibitors. These tumors usually contain billions of cancer cells, and the probability that a drug-resistant subclone preexists in a population of this size is high (6). By contrast, the acquisition of a resistance mutation in the much smaller number of cells that persist during drug treatment has been considered to be comparably low. Drug-induced mutagenesis may shift this balance, providing a compelling argument that resistance can frequently be acquired during treatment (see the figure).

The contribution of drug-induced mutagenesis to clinically acquired resistance in patients with CRC and other cancer types is now important to assess because this remains unclear for several reasons. Mutational processes differ in the preferred DNA sequence contexts in which they occur and in the genetic variants they generate (2). MMR deficiency leads to high rates of deletions in nucleotide repeats and to cytosine-to-thymine base changes. Mutations conferring resistance to EGFR and BRAF inhibitors in CRC are confined to a small number of hotspots in KRAS, NRAS, BRAF, mitogen-activated protein kinase kinase 1 (MEK1), or EGFR genes (78). Whether these specific mutations can be generated by the drug-induced mutagenesis process is unknown. Moreover, there are additional paths to acquired EGFR and BRAF inhibitor resistance beyond mutations, including gene amplifications and an increase of cancer-associated fibroblasts in the tumor microenvironment that rescue cancer cells by secreting mitogenic growth factors (9). Resistance is complicated by the observation that several of these resistance mechanisms can occur in parallel in the same tumor (see the figure). Inhibiting drug-induced mutagenesis to delay resistance evolution will only have clinical impact if this process is the dominant route to resistance in some CRCs.

The DNA repair deficiencies that underlie drug-induced mutagenesis may confer therapeutic vulnerabilities whereby inhibiting another protein or pathway may cause cell death (synthetic lethality). Poly(ADP-ribose) polymerase (PARP) inhibitors are selectively lethal to cancer cells with HR defects due to mutations in the breast cancer 1 (BRCA1) and BRCA2 genes (10). Similarly, the Werner syndrome adenosine triphosphate (ATP)–dependent helicase (WRN) has recently been described as a synthetically lethal target in MMR deficient cancers (11). Whether drug-induced down-regulation of HR or MMR proteins sensitizes CRC cells to PARP or WRN inhibition is unknown but could be readily tested in the cell line models described by Russo et al. Synergies between EGFR inhibition and oxaliplatin chemotherapy have been described (12). Oxaliplatin causes DNA double-strand breaks, which may be difficult to repair when HR is repressed by EGFR inhibition. Some drug combinations in routine clinical use may therefore already exploit the described mechanisms for therapeutic benefit.




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