肾细胞癌舒尼替尼耐药性的机制及治疗研究进展

doi:10.3969/j.issn.1674-8115.2024.10.013

摘要/Abstract

摘要：

肾细胞癌（renal cell carcinoma，RCC）起源于肾小管上皮细胞，是最常见的肾癌类型，也是死亡率最高的泌尿系统肿瘤。近半个世纪以来，RCC的发病率和死亡率持续上升，给人类健康带来了极大的威胁。尽管手术治疗为大多数 RCC 患者提供了治愈的可能，但肿瘤的复发或转移导致传统治疗方案无法达到理想的效果。因此，受体酪氨酸激酶抑制剂和免疫检查点抑制剂等靶向药物的出现，给RCC的治疗带来了新的希望。靶向治疗成为治疗晚期RCC的主要方式。舒尼替尼是一种受体酪氨酸激酶抑制剂，其通过抑制表皮生长因子受体、血小板衍生生长因子受体、血管内皮生长因子受体等多种受体酪氨酸激酶的活性，抑制肿瘤的血管生成和细胞增殖，最终有效控制肿瘤进展，在RCC的治疗中发挥着关键作用。然而，相当多的RCC患者在使用舒尼替尼治疗后的15个月内对其产生耐药性，给RCC的治疗带来了新的挑战。该文总结了RCC舒尼替尼耐药性的发生机制，归纳了RCC舒尼替尼耐药性的治疗策略，以期为克服RCC对舒尼替尼的耐药，给晚期RCC患者制定更有效的治疗方案提供思路。

关键词: 舒尼替尼, 肾细胞癌, 耐药, 代谢重编程, 治疗策略

Abstract:

Renal cell carcinoma (RCC) originates from the epithelial cells of renal tubules and is the most common type of renal cancer, as well as the urological tumor with the highest mortality rate. Over the past half-century, the morbidity and mortality of RCC have been increasing, posing a significant threat to human health. Although surgical treatment offers the possibility of a cure for most RCC patients, tumor recurrence or metastasis leads to the failure of traditional treatment options to achieve the desired results. The advent of targeted drugs, such as receptor tyrosine kinase inhibitors and immune checkpoint inhibitors, has brought new hope for the treatment of RCC. Targeted therapy has become the mainstay of treatment for advanced RCC. Sunitinib is a receptor tyrosine kinase inhibitor that plays a pivotal role in the treatment of RCC. It inhibits the activity of various receptor tyrosine kinases, including epidermal growth factor receptor, platelet-derived growth factor receptor, and vascular endothelial growth factor receptor. This, in turn, inhibits tumor angiogenesis and cellular proliferation, effectively controlling tumor progression. However, a considerable number of RCC patients develop resistance to sunitinib within 15 months of initiating treatment, presenting new challenges for the treatment of RCC. Therefore, this paper summarizes the mechanism of sunitinib resistance in RCC and reviews the treatment of sunitinib resistance in RCC, in order to provide ideas for overcoming the resistance of RCC to sunitinib, and developing a more effective treatment plan for patients with advanced RCC.

Key words: sunitinib, renal cell carcinoma, resistance, metabolic reprogramming, treatment strategy

中图分类号:

R697⁺.32

陈子旋, 刘敏. 肾细胞癌舒尼替尼耐药性的机制及治疗研究进展[J]. 上海交通大学学报（医学版）, 2024, 44(10): 1307-1315.

CHEN Zixuan, LIU Min. Progress in mechanisms and treatment of sunitinib resistance in renal cell carcinoma[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(10): 1307-1315.

图/表 2

图1 肾细胞癌舒尼替尼耐药性的机制Note： MAPK—mitogen-activated protein kinase; ERK—extracellular regulated protein kinase; IL-6—interleukin-6; STAT3—signal transducer and activator of transcription 3; AKT—protein kinase B; VEGF—vascular endothelial growth factor; AXL—AXR1-like; CXCL8—C-X-C motif chemokine ligand 8; ABC—ATP-binding cassette; VLDL—very-low-density lipoprotein; PPP—pentose phosphate pathway; Gln—glutamine; GSH—glutathione; Glu—glutamate; MDSC—myeloid-derived suppressor cell.

Fig 1 Mechanisms of sunitinib resistance in renal cell carcinoma

图2 肾细胞癌舒尼替尼耐药性的治疗

Fig 2 Treatment of sunitinib resistance in renal cell carcinoma

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