A cross-kingdom tale of drug resistance Physicians who treat bacterial infections and those who treat cancer often face a common challenge: the development of drug resistance. It is well known that when bacteria are exposed to antibiotics, they temporarily increase their mutation rate, thus increasing the chance that a descendant antibiotic-resistant cell will arise. Russo et al. now provide evidence that cancer cells exploit a similar mechanism to ensure their survival after drug exposure (see the Perspective by Gerlinger). They found that human colorectal cancer cells treated with certain targeted therapies display a transient up-regulation of errorprone DNA polymerases and a reduction in their ability to repair DNA damage. Thus, like bacteria, cancer cells can adapt to therapeutic pressure by enhancing their mutability. Science, this issue p. 1473; see also p. 1458 Cancer cells can evade therapeutic pressure by increasing their mutation rate. 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.

中文翻译：

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结肠直肠癌对靶向治疗的适应性变异

耐药性的跨界故事 治疗细菌感染的医生和治疗癌症的医生经常面临一个共同的挑战：耐药性的发展。众所周知，当细菌接触抗生素时，它们的突变率会暂时增加，从而增加产生抗生素耐药细胞后代的机会。鲁索等人。现在提供证据表明癌细胞利用类似的机制来确保药物暴露后它们的存活（参见 Gerlinger 的观点）。他们发现，用某些靶向疗法治疗的人类结直肠癌细胞显示出易错 DNA 聚合酶的瞬时上调，并降低了它们修复 DNA 损伤的能力。因此，与细菌一样，癌细胞可以通过增强其可变性来适应治疗压力。科学，这个问题 p。第1473章 另见第。1458 癌细胞可以通过增加突变率来逃避治疗压力。耐药性的出现限制了靶向治疗在人类肿瘤中的疗效。普遍的观点是耐药性是既成事实：当开始治疗时，癌症已经包含耐药性突变细胞。接触抗生素的细菌会暂时增加它们的突变率（适应性可变性），从而提高存活的可能性。我们研究了人类结直肠癌 (CRC) 细胞是否同样利用适应性可变性来逃避治疗压力。我们发现表皮生长因子受体 (EGFR)/BRAF 抑制下调错配修复 (MMR) 和同源重组 DNA 修复基因，同时上调耐药（持久）细胞中的易错聚合酶。在治疗期间，患者来源的异种移植物和肿瘤标本中的 MMR 蛋白也被下调。EGFR/BRAF 抑制诱导 DNA 损伤，增加可变性，并引发微卫星不稳定性。因此，与单细胞生物一样，肿瘤细胞通过增强可变性来逃避治疗压力。