靶向EGFR蛋白降解剂及其在非小细胞肺癌中的应用

doi:10.3969/j.issn.0253-9608.2021.06.002

自然杂志 ›› 2021, Vol. 43 ›› Issue (6): 400-407.doi: 10.3969/j.issn.0253-9608.2021.06.002

靶向EGFR蛋白降解剂及其在非小细胞肺癌中的应用

宋肖玲^①，屈小娟^①②，曲思琪^①② ，姜标^①③

①上海科技大学免疫化学研究所，上海 201210；②上海科技大学生命科学与技术学院，上海 201210；③中国科学院上海有机化学研究所，上海 200032

收稿日期:2021-05-29 出版日期:2021-10-25 发布日期:2021-10-25
通讯作者: 姜标，通信作者，国家杰出青年科学基金获得者，国际欧亚科学院院士，研究方向：有机化学。

Novel strategies to target EGFR proteins for degradation and their applications in non-small cell lung cancer

SONG Xiaoling^① , QU Xiaojuan^①② , QU Siqi^①② , JIANG Biao^①③

①Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China; ②School of Life
Science and Technology, ShanghaiTech University, Shanghai 201210, China; ③Shanghai Institute of Organic Chemistry, Chinese
Academy of Sciences, Shanghai 200032, China

Received:2021-05-29 Online:2021-10-25 Published:2021-10-25

摘要/Abstract

摘要： 细胞表皮生长因子受体(EGFR)突变是引起部分非小细胞肺癌(NSCLC)发病的一个主要原因。目前，临床上对具有EGFR突变的NSCLC患者使用的标准治疗方案是使用靶向EGFR的酪氨酸激酶小分子抑制剂药物。然而，患者使用此类小分子抑制剂药物后不可避免地会出现耐药现象，因此临床亟需发展新的技术来克服耐药现象，提升靶向治疗的长期疗效。由于EGFR突变肺癌以及此类肺癌对靶向药物产生耐药后对EGFR突变蛋白具有高度的依赖性，开发新型蛋白降解剂特异性地降解EGFR致病蛋白为治疗肺癌和克服肿瘤耐药提供了一种极有潜力的解决途径。目前，已经有多种靶向EGFR蛋白降解的策略用于清除肺癌细胞中的EGFR蛋白，包括靶向蛋白降解技术(PROTAC)、溶酶体靶向降解技术(LYTAC)和基于EGFR和TRIB3相互作用的订书肽。文章主要就上述三种技术在EGFR蛋白靶向降解中的研究进展进行综述，并对其在NSCLC治疗中的潜在应用进行探讨。

关键词: 靶向蛋白降解技术, EGFR 突变, 非小细胞肺癌, 靶向蛋白降解, 耐药, 溶酶体靶向降解技术

Abstract: Activating mutations in the kinase domains of EGFR (epidermal growth factor receptor) lead into the occurrence of non-small cell lung cancer. Currently, the standard care for such diseases is to use EGFR-specific tyrosine kinase inhibitor drugs. However,
drug resistance inevitably occurs after the treatment with these drugs. Novel strategies are needed to solve these issues to extend
patients survival time. Due to the dependency of EGFR mutant lung cancer on EGFR proteins and the critical roles of EGFR protein
in drug resistance, targeted degradation of EGFR protein provides a promising strategy to treat such patients. Several novel strategies have been developed lately to target EGFR for degradation in non-small cell lung cancer. The strategies include proteolysis targeting chimeras (PROTACs), lysosome-targeting chimaera (LYTAC) and stapled-peptide. The latest development of these strategies were reviewed and their potential uses in lung cancer treatment were assessed.

Key words: proteolysis targeting chimera (PROTAC), EGFR mutation, non-small cell lung cancer, targeted degradation, drug , resistance, lysosome-targeting chimaera (LYTAC)

宋肖玲, 屈小娟, 曲思琪, 姜标. 靶向EGFR蛋白降解剂及其在非小细胞肺癌中的应用[J]. 自然杂志, 2021, 43(6): 400-407.

SONG Xiaoling , QU Xiaojuan , QU Siqi , JIANG Biao. Novel strategies to target EGFR proteins for degradation and their applications in non-small cell lung cancer[J]. Chinese Journal of Nature, 2021, 43(6): 400-407.

参考文献

[1]　CARPENTER G, COHEN S. Epidermal growth factor [J]. Journal of Biological Chemistry, 1990, 265(14): 7709-7712.
[2]　PAO W, MILLER V A. Epidermal growth factor receptor mutations, small-molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge and future directions [J]. J Clin Oncol, 2005, 23(11): 2556-2568.
[3]　RITTER C A, ARTEAGA C L. The epidermal growth factor receptor-tyrosine kinase: a promising therapeutic target in solid
tumors [J]. Semin Oncol, 2003, 30(S1): 3-11.
[4]　YATABE Y, KERR K M, UTOMO A, et al. EGFR mutation testing practices within the Asia Pacific region: results of a multicenter
diagnostic survey [J]. J Thorac Oncol, 2015, 10(3): 438-445.
[5]　ROSELL R, MORAN T, QUERALT C, et al. Screening for epidermal growth factor receptor mutations in lung cancer [J]. NEngl J Med, 2009, 361(10): 958-967.
[6]　ANGELO S P, PIETANZA M C, JOHNSON M L, et al. Incidence of EGFR exon 19 deletions and L858R in tumor specimens from
men and cigarette smokers with lung adenocarcinomas [J]. J Clin Oncol, 2011, 29(15): 2066-2070.
[7]　The Cancer Genome Atlas Research Network. Comprehensive molecular profiling of lung adenocarcinoma [J]. Nature, 2014,
511(7511): 543-550.
[8]　SHI Y, AU J S, THONGPRASERT S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER) [J]. J Thorac Oncol, 2014, 9(2): 154-162.
[9]　TSAO A S, TANG X M, SABLOFF B, et al. Clinicopathologic characteristics of the EGFR gene mutation in non-small cell lung
cancer [J]. J Thorac Oncol, 2006, 1(3): 231-239.
[10] SKOV B G, HOGDALL E, CLEMENTSEN P, et al. The prevalence of EGFR mutations in non-small cell lung cancer in an unselected Caucasian population [J]. APMIS, 2015, 123(2): 108-115.
[11] SHTIEGMAN K, KOCHUPURAKKAL B S, ZWANG Y, et al. Defective ubiquitinylation of EGFR mutants of lung cancer confers
prolonged signaling [J]. Oncogene, 2007, 26(49): 6968-6978.
[12] LYNCH T J, BELL D W, SORDELLA R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib [J]. N Engl J Med, 2004, 350(21): 2129-2139.
[13] MITSUDOMI T, KOSAKA T, ENDOH H, et al. Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence [J]. J Clin Oncol, 2005, 23(11): 2513-2520.
[14] ARCILA M E, OXNARD G R, NAFA K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and
enhanced detection of the T790M mutation using a locked nucleic acid-based assay [J]. Clin Cancer Res, 2011, 17(5): 1169-1180.
[15] MÉNARD L, FLOC'H N, MARTIN M J, et al. Reactivation of mutant-EGFR degradation through Clathrin inhibition overcomes
resistance to EGFR tyrosine kinase inhibitors [J]. Cancer Research, 2018, 78(12): 3267-3279.
[16] YAO N, WANG C R, LIU M Q, et al. Discovery of a novel EGFR ligand DPBA that degrades EGFR and suppresses EGFR-positive
NSCLC growth [J]. Signal Transduction and Targeted Therapy, 2020, 5(1): 214.
[17] SAKAMOTO K M, KIM K B, KUMAGAI A, et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box
complex for ubiquitination and degradation [J]. Proc Natl Acad Sci USA, 2001, 98(15): 8554-8559.
[18] HOCHSTRASSER M. Ubiquitin, proteasomes, and the regulation of intracellular protein degradation [J]. Current Opinion in Cell
Biology, 1995, 7(2): 215-223.
[19] LIU J, MA J, LIU Y, et al. PROTACs: a novel strategy for cancer therapy [J]. Semin Cancer Biol, 2020, 67: 171-179.
[20] SUN X, GAO H, YANG Y, et al. PROTACs: great opportunities for academia and industry [J]. Sig Transduct Target Ther, 2019, 4: 64.
[21] CHENG M, YU X, LU K, et al. Discovery of potent and selective epidermal growth factor receptor (EGFR) bifunctional small-
molecule degraders [J]. J Med Chem, 2020, 63(3): 1216-1232.
[22] HE K, ZHANG Z, WANG W, et al. Discovery and biological evaluation of proteolysis targeting chimeras (PROTACs) as an
EGFR degraders based on osimertinib and lenalidomide [J]. Bioorg Med Chem Lett, 2020, 30(12): 127167.
[23] QU X, LIU H, SONG X, et al. Effective degradation of EGFRL858R+T790M mutant proteins by CRBN-based PROTACs
through both proteosome and autophagy/lysosome degradation systems [J]. Eur J Med Chem, 2021, 218(2): 113328.
[24] ZHANG H, ZHAO H Y, XI X X, et al. Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC) [J]. Eur J Med Chem, 2020, 189: 112061.
[25] ZHANG X, XU F, TONG L, et al. Design and synthesis of selective degraders of EGFR(L858R/T790M) mutant [J]. Eur J Med Chem, 2020, 192: 112199.
[26] BURSLEM G M, SMITH B E, LAI A C, et al. The advantages of targeted protein degradation over inhibition: An RTK case study [J]. Cell Chem Biol, 2018, 25(1): 67-77. e3.
[27] ZHAO H Y, YANG X Y, LEI H, et al. Discovery of potent small molecule PROTACs targeting mutant EGFR [J]. Eur J Med Chem,
2020, 208: 112781.
[28] BANIK S M, PEDRAM K, WISNOVSKY S, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins [J].
Nature, 2020, 584(7820): 291-297.
[29] COUTINHO M F, PRATA M J, ALVES S. A shortcut to the lysosome: the mannose-6-phosphate-independent pathway [J]. Mol
Genet Metab, 2012, 107(3): 257-266.
[30] GHOSH P, DAHMS N M, KORNFELD S. Mannose 6-phosphate receptors: new twists in the tale [J]. Nat Rev Mol Cell Biol, 2003,
4(3): 202-212.
[31] BRAULKE T, BONIFACINO J S. Sorting of lysosomal proteins [J].Biochim Biophys Acta, 2009, 1793(4): 605-614.
[32] KYLE J W, NOLAN C M, OSHIMA A, et al. Expression of human cation-independent mannose 6-phosphate receptor cDNA in
receptor-negative mouse P388D1 cells following gene transfer [J]. Journal of Biological Chemistry, 1988, 263(31): 16230-16235.
[33] LOBEL P, FUJIMOTO K, YE R D, et al. Mutations in the cytoplasmic domain of the 275 kd mannose 6-phosphate receptor
differentially alter lysosomal enzyme sorting and endocytosis [J]. Cell, 1989, 57(5): 787-796.
[34] STEIN M, ZIJDERHAND-BLEEKEMOLEN J E, GEUZE H, et al. Mr 46,000 mannose 6-phosphate specific receptor: its role in
targeting of lysosomal enzymes [J]. EMBO J, 1987, 6(9): 2677-2681.
[35] MOIOLA M, MEMEO M G, QUADRELLI P. Stapled peptides—a useful improvement for peptide-based drugs [J]. Molecules, 2019, 24(20): 3654.
[36] LAU Y H, DE ANDRADE P, QUAH S-T, et al. Functionalised staple linkages for modulating the cellular activity of stapled peptides [J]. Chem Sci, 2014, 5(5): 1804-1809.
[37] WALENSKY L D, BIRD G H. Hydrocarbon-stapled peptides: principles, practice, and progress [J]. J Med Chem, 2014, 57(15):
6275-6288.
[38] YU J J, ZHOU D D, YANG X X, et al. TRIB3-EGFR interaction promotes lung cancer progression and defines a therapeutic target [J]. Nat Commun, 2020, 11(1): 3660.
[39] TAKAHASHI D, MORIYAMA J, NAKAMURA T, et al. AUTACs: Cargo-specific degraders using selective autophagy [J]. Mol Cell,
2019, 76(5): 797-810. e10.
[40] LI Z, WANG C, WANG Z, et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds [J]. Nature, 2019, 575(7781): 203-209.
[41] TAKAHASHI D, ARIMOTO H. Targeting selective autophagy by AUTAC degraders [J]. Autophagy, 2020, 16(4): 765-766.

靶向EGFR蛋白降解剂及其在非小细胞肺癌中的应用

Novel strategies to target EGFR proteins for degradation and their applications in non-small cell lung cancer

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 0

编辑推荐

Metrics

本文评价