Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Clinical Sciences Building, Parkville, VIC 3050, Australia.
Fiona Elsey Cancer Research Institute, Federation University Australia, Ballarat, VIC 3350, Australia.
Int J Mol Sci. 2021 Jul 1;22(13):7114. doi: 10.3390/ijms22137114.
Cetuximab is a common treatment option for patients with wild-type K-Ras colorectal carcinoma. However, patients often display intrinsic resistance or acquire resistance to cetuximab following treatment. Here we generate two human CRC cells with acquired resistance to cetuximab that are derived from cetuximab-sensitive parental cell lines. These cetuximab-resistant cells display greater in vitro proliferation, colony formation and migration, and in vivo tumour growth compared with their parental counterparts. To evaluate potential alternative therapeutics to cetuximab-acquired-resistant cells, we tested the efficacy of 38 current FDA-approved agents against our cetuximab-acquired-resistant clones. We identified carfilzomib, a selective proteosome inhibitor to be most effective against our cell lines. Carfilzomib displayed potent antiproliferative effects, induced the unfolded protein response as determined by enhanced CHOP expression and ATF6 activity, and enhanced apoptosis as determined by enhanced caspase-3/7 activity. Overall, our results indicate a potentially novel indication for carfilzomib: that of a potential alternative agent to treat cetuximab-resistant colorectal cancer.
西妥昔单抗是野生型 K-Ras 结直肠癌患者的常用治疗选择。然而，患者在治疗后常常表现出内在耐药或获得对西妥昔单抗的耐药性。在这里，我们生成了两种源自西妥昔单抗敏感亲本细胞系的获得性对西妥昔单抗耐药的人 CRC 细胞。与亲本细胞相比，这些西妥昔单抗耐药细胞在体外增殖、集落形成和迁移以及体内肿瘤生长方面表现出更强的能力。为了评估针对西妥昔单抗获得性耐药细胞的潜在替代治疗方法，我们测试了 38 种当前 FDA 批准的药物对我们的西妥昔单抗获得性耐药克隆的疗效。我们发现，选择性蛋白酶体抑制剂卡非佐米对我们的细胞系最有效。卡非佐米显示出强大的抗增殖作用，如 CHOP 表达和 ATF6 活性增强所确定的未折叠蛋白反应，以及 caspase-3/7 活性增强所确定的细胞凋亡增强。总的来说，我们的结果表明卡非佐米可能有一个新的适应症：作为治疗西妥昔单抗耐药结直肠癌的潜在替代药物。
