Colorectal cancer (CRC) is one of the most diagnosed cancers and a leading contributor to cancer-related deaths in the United States. Clinically, standard treatment regimens include surgery, radiation, and chemotherapy; however, there has been increasing development and clinical use of targeted therapies for CRC. Unfortunately, many patients develop resistance to these treatments. Cetuximab, the first targeted therapy approved to treat advanced CRC, is a monoclonal antibody that targets the epidermal growth factor receptor and inhibits downstream pathway activation to restrict tumor cell growth and proliferation. CRC resistance to cetuximab has been well studied, and common resistance mechanisms include constitutive signal transduction through downstream protein mutations and promotion of the epithelial-to-mesenchymal transition. While the most common resistance mechanisms are known, a proportion of patients develop resistance through unknown mechanisms. One protein predicted to contribute to therapy resistance is RAC1, a small GTPase that is involved in cytoskeleton rearrangement, cell migration, motility, and proliferation. RAC1 has also been shown to be overexpressed in CRC. Despite evidence that RAC1 and its alternative splice isoform RAC1B play important roles in CRC and the pathways known to contribute to cetuximab resistance, there is a need to directly study the relationship between RAC1 and RAC1B and cetuximab resistance. This review highlights the recent studies investigating RAC1 and RAC1B in the context of CRC and suggests that these proteins could play a role in resistance to cetuximab.
结直肠癌是美国诊断率最高的癌症之一，也是导致癌症相关死亡的主要原因。临床上，标准治疗方案包括手术、放疗和化疗；然而，针对结直肠癌的靶向疗法在研发和临床应用方面日益增多。遗憾的是，许多患者对这些治疗产生了耐药性。西妥昔单抗作为首个获批用于治疗晚期结直肠癌的靶向药物，是一种靶向表皮生长因子受体的单克隆抗体，通过抑制下游通路激活来限制肿瘤细胞的生长和增殖。结直肠癌对西妥昔单抗的耐药机制已得到充分研究，常见的耐药机制包括通过下游蛋白突变产生的持续信号转导以及上皮-间质转化的促进。尽管最常见的耐药机制已被认知，仍有一部分患者通过未知机制产生耐药性。RAC1蛋白被预测与治疗耐药相关，这是一种参与细胞骨架重组、细胞迁移、运动与增殖的小GTP酶。研究已证实RAC1在结直肠癌中存在过表达现象。尽管有证据表明RAC1及其选择性剪接异构体RAC1B在结直肠癌中发挥重要作用，且其参与的通路已知与西妥昔单抗耐药相关，但仍需直接研究RAC1、RAC1B与西妥昔单抗耐药之间的关联。本综述重点探讨了近期关于RAC1和RAC1B在结直肠癌中的研究进展，并提出这两种蛋白可能在介导西妥昔单抗耐药中发挥作用。
肿瘤(癌症)患者之家