Medical Oncology Branch, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.
Anticancer Agents Med Chem. 2011 Feb;11(2):242-6. doi: 10.2174/187152011795255948.
A concept that currently steers the development of cancer therapies has been that agents directed against specific proteins that facilitate tumorigenesis or maintain a malignant phenotype will have greater efficacy, less toxicity and a more sustained response relative to traditional cytotoxic chemotherapeutic agents. The clinical success of the targeted agent Imatinib mesylate as an inhibitor of the tyrosine kinase associated with the breakpoint cluster region-Abelson oncogene locus (BCR-ABL) in the treatment of Philadelphia-positive chronic myelogenous leukemia (CML) has served as a paradigm. While intellectually gratifying, the selective targeting of a single driver event by a small molecule, e.g., kinase inhibitor, to dampen a tumor-promoting pathway in the treatment of solid tumors is limited by many factors. Focus can alternatively be placed on targeting fundamental cellular processes that regulate multiple events, e.g., protein degradation, through the Ubiquitin (Ub)+Proteasome System (UPS). The UPS plays a critical role in modulating numerous cellular proteins to regulate cellular processes such as signal transduction, growth, proliferation, differentiation and apoptosis. Clinical success with the proteasome inhibitor bortezomib revolutionized treatment of B-cell lineage malignancies such as Multiple Myeloma (MM). However, many patients harbor primary resistance and do not respond to bortezomib and those that do respond inevitably develop resistance (secondary resistance). The lack of clinical efficacy of proteasome inhibitors in the treatment of solid tumors may be linked mechanistically to the resistance detected during treatment of hematologic malignancies. Potential mechanisms of resistance and means to improve the response to proteasome inhibitors in solid tumors are discussed.
目前，癌症治疗的发展方向是，针对促进肿瘤发生或维持恶性表型的特定蛋白质的药物，与传统细胞毒性化疗药物相比，将具有更高的疗效、更低的毒性和更持久的反应。靶向药物伊马替尼甲磺酸盐作为与费城阳性慢性髓性白血病（CML）中的断裂点簇区-Abelson 致癌基因座（BCR-ABL）相关的酪氨酸激酶抑制剂的临床成功就是一个范例。虽然从理论上令人满意，但通过小分子（例如激酶抑制剂）选择性靶向单一驱动事件来抑制实体瘤中促进肿瘤的途径受到许多因素的限制。替代方法是专注于靶向调节多种事件的基本细胞过程，例如通过泛素（Ub）+蛋白酶体系统（UPS）进行蛋白质降解。UPS 在调节许多细胞蛋白以调节细胞过程（如信号转导、生长、增殖、分化和凋亡）方面起着至关重要的作用。蛋白酶体抑制剂硼替佐米在治疗 B 细胞谱系恶性肿瘤（如多发性骨髓瘤（MM））方面的临床成功彻底改变了治疗方法。然而，许多患者存在原发性耐药性，对硼替佐米无反应，而那些有反应的患者不可避免地会产生耐药性（继发性耐药性）。蛋白酶体抑制剂在实体瘤治疗中的临床疗效不佳可能与在血液恶性肿瘤治疗中检测到的耐药性在机制上有关。讨论了耐药性的潜在机制以及改善蛋白酶体抑制剂在实体瘤中的反应的方法。
