{"id":4925,"date":"2020-01-07T19:20:54","date_gmt":"2020-01-07T10:20:54","guid":{"rendered":"http:\/\/163.180.4.222\/lab\/?p=4925"},"modified":"2020-01-07T19:20:54","modified_gmt":"2020-01-07T10:20:54","slug":"targeted-drugs-ramp-up-cancer-mutability","status":"publish","type":"post","link":"https:\/\/biochemistry.khu.ac.kr\/lab\/?p=4925","title":{"rendered":"Targeted drugs ramp up cancer mutability"},"content":{"rendered":"

 <\/p>\n

 <\/p>\n

Mutagenesis can drive carcinogenesis and continue during cancer progression, generating genetic intratumor heterogeneity that enables cancer adaptation through Darwinian evolution (1<\/em><\/a>). Analyses, such as mutational signature characterization, have revealed specific mutational processes and their temporal activity during carcinogenesis and tumor progression (2<\/em><\/a>). Nevertheless, many of the mechanisms that promote genomic instability in cancer are still enigmatic. On page 1473 of this issue, Russo\u00a0et al.<\/em>\u00a0(3<\/em><\/a>) 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.<\/p>\n

Russo\u00a0et al.<\/em>\u00a0found 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\u2014such 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<\/em><\/a>)\u2014the mutagenesis program identified by Russo\u00a0et al.<\/em>\u00a0was 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.<\/p>\n

Adaptive mutagenesis is a mechanism described in bacteria that increases the mutation rate in response to cell stress (5<\/em><\/a>). 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\u00a0et al.<\/em>\u00a0explored 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.<\/p>\n

Russo\u00a0et al.<\/em>\u00a0speculate 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.<\/p>\n

 <\/p>\n

\n
\n
<\/span><\/a><\/div>\n
\n