Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, Texas.
Mol Cancer Res. 2019 Nov;17(11):2196-2207. doi: 10.1158/1541-7786.MCR-19-0436. Epub 2019 Aug 23.
Drug resistance continues to be a major obstacle of effective therapy for colorectal cancer, leading to tumor relapse or treatment failure. Cancer stem cells (CSC) or tumor-initiating cells are a subpopulation of tumor cells which retain the capacity for self-renewal and are suggested to be implicated in drug resistance. LGR5 is highly expressed in colorectal cancer and marks CSCs that drive tumor growth and metastasis. LGR5() CSCs cells were shown to interconvert with more drug-resistant LGR5() cancer cells, and treatment with LGR5-targeted antibody-drug conjugates (ADC) eliminated LGR5() tumors, yet a fraction of LGR5() tumors eventually recurred. Therefore, it is important to identify mechanisms associated with CSC plasticity and drug resistance in order to develop curative therapies. Here, we show that loss of LGR5 in colon cancer cells enhanced resistance to irinotecan and 5-fluorouracil and increased expression of adhesion G-protein-coupled receptor, GPR56. expression was significantly higher in primary colon tumors versus matched normal tissues and correlated with poor survival outcome. GPR56 enhanced drug resistance through upregulation of MDR1 levels via a RhoA-mediated signaling mechanism. Loss of GPR56 led to suppression of tumor growth and increased sensitivity of cancer cells to chemotherapy and monomethyl auristatin E-linked anti-LGR5 ADCs, by reducing MDR1 levels. These findings suggest that upregulation of GPR56 may be a mechanism associated with CSC plasticity by which LGR5() cancer cells acquire a more drug-resistant phenotype. IMPLICATIONS: Our findings suggest that targeting GPR56 may provide a new strategy for the treatment of colorectal cancer and combatting drug resistance.
耐药性仍然是结直肠癌有效治疗的主要障碍，导致肿瘤复发或治疗失败。癌症干细胞（CSC）或肿瘤起始细胞是肿瘤细胞的一个亚群，它们保留自我更新的能力，并被认为与耐药性有关。LGR5 在结直肠癌中高度表达，并标记驱动肿瘤生长和转移的 CSCs。已经表明，LGR5()CSC 细胞可以与更耐药的 LGR5()癌细胞相互转化，并且用 LGR5 靶向抗体药物偶联物（ADC）治疗可以消除 LGR5()肿瘤，但一部分 LGR5()肿瘤最终会复发。因此，确定与 CSC 可塑性和耐药性相关的机制对于开发治愈性疗法非常重要。在这里，我们表明，结肠癌细胞中 LGR5 的缺失增强了对伊立替康和 5-氟尿嘧啶的耐药性，并增加了黏附 G 蛋白偶联受体 GPR56 的表达。在原发性结肠肿瘤与匹配的正常组织相比，表达明显更高，与不良生存结局相关。GPR56 通过 RhoA 介导的信号机制上调 MDR1 水平来增强耐药性。GPR56 的缺失导致肿瘤生长受到抑制，并且由于 MDR1 水平降低，癌细胞对化疗和单甲基奥瑞他汀 E 连接的抗 LGR5 ADC 的敏感性增加。这些发现表明，GPR56 的上调可能是与 LGR5()癌细胞获得更耐药表型的 CSC 可塑性相关的机制之一。意义：我们的发现表明，靶向 GPR56 可能为治疗结直肠癌和对抗耐药性提供一种新策略。
