结直肠癌 (CRC) 是一种通过遗传多样性和克隆演化的连续过程产生的肿瘤。多个基因和通路在肿瘤初始化和进展中发挥作用。逐渐积累的遗传和表观基因过程导致腺瘤和癌症的形成。肿瘤抑制基因 (如 TP53、APC 和 SMAD4) 和致癌基因 (如 KRAS、NRAS、MET 和 PIK3CA) 中的重要“驱动”突变赋予肿瘤选择性增长优势并导致 CRC 的进展。治疗压力诱导的克隆演化以及肿瘤内部的异质性是治疗转移性 CRC 的巨大挑战。由于肿瘤内部的异质性、克隆演化和选择，肿瘤经常会对治疗产生抗性。因此，应优先开发多药个性化方法，为治疗重新定位和联合疗法铺平道路，以阻止肿瘤进展。本文总结了选择性药物压力如何影响肿瘤演化，导致多克隆抵抗机制的形成，最终促进癌症进展。还描述了针对克隆演化的当前策略。通过理解肿瘤异质性的来源和后果，可以制定定制和有效的治疗计划来对抗药物抗性。版权所有 ©2022 Elsevier B.V.。

Colorectal cancer (CRC) arises by a continuous process of genetic diversification and clonal evolution. Multiple genes and pathways have a role in tumor initiation and progression. The gradual accumulation of genetic and epigenetic processes leads to the establishment of adenoma and cancer. The important 'driver' mutations in tumor suppressor genes (such as TP53, APC, and SMAD4) and oncogenes (such as KRAS, NRAS, MET, and PIK3CA) confer selective growth advantages and cause CRC advancement. Clonal evolution induced by therapeutic pressure, as well as intra-tumoral heterogeneity, has been a great challenge in the treatment of metastatic CRC. Tumors often develop resistance to treatments as a result of intra-tumor heterogeneity, clonal evolution, and selection. Hence, the development of a multidrug personalized approach should be prioritized to pave the way for therapeutics repurposing and combination therapy to arrest tumor progression. This review summarizes how selective drug pressure can impact tumor evolution, resulting in the formation of polyclonal resistance mechanisms, ultimately promoting cancer progression. Current strategies for targeting clonal evolution are described. By understanding sources and consequences of tumor heterogeneity, customized and effective treatment plans to combat drug resistance may be devised.Copyright © 2022 Elsevier B.V. All rights reserved.