Candiolo Cancer Institute-FPO, IRCCS, 10060, Candiolo, Turin, Italy.
Department of Oncology, University of Torino, SP 142 km 3.95, 10060, Candiolo, Turin, Italy.
Nat Commun. 2018 Jun 12;9(1):2287. doi: 10.1038/s41467-018-04506-z.
Attempts at eradicating metastatic cancers with targeted therapies are limited by the emergence of resistant subclones bearing heterogeneous (epi)genetic changes. We used colorectal cancer (CRC) to test the hypothesis that interfering with an ancestral oncogenic event shared by all the malignant cells (such as WNT pathway alterations) could override heterogeneous mechanisms of acquired drug resistance. Here, we report that in CRC-resistant cell populations, phylogenetic analysis uncovers a complex subclonal architecture, indicating parallel evolution of multiple independent cellular lineages. Functional and pharmacological modulation of WNT signalling induces cell death in CRC preclinical models from patients that relapsed during the treatment, regardless of the drug type or resistance mechanisms. Concomitant blockade of WNT and MAPK signalling restrains the emergence of drug-resistant clones. Reliance upon the WNT-APC pathway is preserved throughout the branched genomic drift associated with emergence of treatment relapse, thus offering the possibility of a common therapeutic strategy to overcome secondary drug resistance.
试图用靶向治疗根除转移性癌症受到限制，因为具有异质性（表观遗传学）遗传变化的耐药亚克隆的出现。我们使用结直肠癌（CRC）来测试这样一个假设，即干扰所有恶性细胞共有的祖源致癌事件（如 WNT 途径改变）可以克服获得性耐药的异质机制。在这里，我们报告在 CRC 耐药细胞群中，系统发生分析揭示了一种复杂的亚克隆结构，表明多个独立细胞谱系的平行进化。在接受治疗期间复发的 CRC 临床前模型中，WNT 信号的功能和药理学调节诱导细胞死亡，而与药物类型或耐药机制无关。WNT 和 MAPK 信号的同时阻断抑制耐药克隆的出现。在与治疗复发相关的分支基因组漂移过程中，对 WNT-APC 途径的依赖得以保留，从而为克服继发性耐药提供了一种共同的治疗策略的可能性。
