近日，意大利都灵大学Alberto Bardelli、Mariangela Russo等研究人员合作揭示了结肠直肠癌对靶向疗法的适应性变异。2019年11月7日，《科学》在线发表了这一研究成果。
研究人员调查了人类结直肠癌（CRC）细胞是否同样利用自适应变异性来规避治疗压力。研究人员发现，表皮生长因子受体（EGFR）/BRAF抑制作用能够下调错配修复（MMR）和同源重组（HR）DNA修复基因，并同时上调药物耐受性（persister）细胞中易错的聚合酶。在治疗期间，源自患者的异种移植物和肿瘤标本中的MMR蛋白也下调。EGFR/BRAF抑制能够诱导DNA损伤，增加变异性并触发微卫星不稳定性。因此，像单细胞生物一样，肿瘤细胞通过增强变异性来躲避治疗压力。
研究人员表示，耐药性的出现限制了靶向疗法在人类肿瘤中的功效。目前普遍的看法认为耐药是既成事实：开始治疗时，癌症已经含有耐药性突变细胞。暴露于抗生素的细菌会暂时增加其突变率（自适应变异性），从而提高了生存的可能性。
附：英文原文
Title: Adaptive mutability of colorectal cancers in response to targeted therapies
Author: Mariangela Russo, Giovanni Crisafulli, Alberto Sogari, Nicole M. Reilly, Sabrina Arena, Simona Lamba, Alice Bartolini, Vito Amodio, Alessandro Magrì, Luca Novara, Ivana Sarotto, Zachary D. Nagel, Cortt G. Piett, Alessio Amatu, Andrea Sartore-Bianchi, Salvatore Siena, Andrea Bertotti, Livio Trusolino, Mattia Corigliano, Marco Gherardi, Marco Cosentino Lagomarsino, Federica Di Nicolantonio, Alberto Bardelli
Issue&Volume: 2019/11/07
Abstract: AbstractThe 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 (HR) 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.
DOI: 10.1126/science.aav4474
Source: https://science.sciencemag.org/content/early/2019/11/06/science.aav4474