从“合成致死”策略的视角浅谈头颈鳞癌靶向治疗

doi:10.19438/j.cjoms.2021.03.019

摘要/Abstract

摘要： 合成致死指在2个基因中,单独1个基因发生功能性缺失不影响细胞存活,但是2个基因同时发生功能性缺失,能够特异性诱导细胞死亡。头颈鳞癌是以抑癌基因高频突变为特征的恶性肿瘤,利用合成致死能够为该类靶向药物匮乏的肿瘤提供全新的治疗策略。得益于RNA干扰技术和CRISPR/Cas9基因编辑技术的发展,肿瘤合成致死筛选变得更加精准高效,开辟了全基因组范围内筛选抗肿瘤合成致死新靶点,完善了联合用药方案和逆转肿瘤免疫逃逸等治疗策略。由于合成致死具有强烈的遗传背景依赖性,人源性肿瘤异种移植瘤模型能够充分反映肿瘤异质性和患者的遗传学背景,是进行合成致死筛选和验证的理想临床前模型。

关键词: 合成致死, 头颈鳞癌, 抑癌基因, 靶向治疗

Abstract: Synthetic lethality occurs between two genes when loss of function of either gene is viable but loss of function of both genes simultaneously specifically induces cell death. Head and neck squamous cell carcinoma (HNSCC) is a malignant tumor characterized by high-frequency mutations of tumor suppressor genes, and synthetic lethality has the potential to provide a novel therapeutic strategy for HNSCC which lacks of targeted drugs. With the development of RNA interfering and CRISPR/Cas9-mediated gene editing technology, synthetic lethal screening tends to be more accurate and efficient to explore therapeutic approach including screening novel anti-tumor targets at the whole genome region, refining combination drug therapy and reversing tumor immune escape. Considering genetic context significantly influences synthetic lethality, patient-derived xenograft (PDX) model performs as an ideal preclinical model for screening and verifying synthetic lethality, because it can fully reflect tumor heterogeneity and genetic background of patients.

Key words: Synthetic lethality, Head and neck squamous cell carcinoma, Tumor suppressor gene, Targeted therapy

中图分类号:

R739.8

陈澜, 张志愿, 孙树洋. 从“合成致死”策略的视角浅谈头颈鳞癌靶向治疗[J]. 中国口腔颌面外科杂志, 2021, 19(3): 278-283.

CHEN Lan, ZHANG Zhi-yuan, SUN Shu-yang. Synthetic lethality: towards the targeted strategies of head and neck squamous cell carcinoma[J]. China J Oral Maxillofac Surg, 2021, 19(3): 278-283.

参考文献

[1] Chi AC, Day TA, Neville BW.Oral cavity and oropharyngeal squamous cell carcinoma-an update[J]. CA Cancer J Clin, 2015, 65(5): 401-421.
[2] Vermorken JB, Trigo J, Hitt R, et al.Open-label, uncontrolled, multicenter phase Ⅱ study to evaluate the efficacy and toxicity of cetuximab as a single agent in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck who failed to respond to platinum-based therapy[J]. J Clin Oncol, 2007, 25(16): 2171-2177.
[3] Ferris RL, Blumenschein G Jr, Fayette J, et al.Nivolumab for recurrent squamous-cell carcinoma of the head and neck[J]. N Engl J Med, 2016, 375(19): 1856-1867.
[4] Seiwert TY, Burtness B, Mehra R, et al.Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial[J]. Lancet Oncol, 2016, 17(7): 956-965.
[5] Mehanna H, Robinson M, Hartley A, et al.Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial[J]. Lancet, 2019, 393(10166): 51-60.
[6] Burtness B, Harrington KJ, Greil R, et al.Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study[J]. Lancet, 2019, 394(10212): 1915-1928.
[7] Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas[J]. Nature, 2015, 517(7536): 576-582.
[8] Nijman SMB, Friend SH.Cancer. Potential of the synthetic lethality principle[J]. Science, 2013, 342(6160): 809-811.
[9] Dobzhansky T.Genetics of natural populations; recombination and variability in populations of Drosophila pseudoobscura[J]. Genetics, 1946, 31(3): 269-290.
[10] Hartwell LH, Szankasi P, Roberts CJ, et al.Integrating genetic approaches into the discovery of anticancer drugs[J]. Science, 1997, 278(5340): 1064-1068.
[11] Bryant HE, Schultz N, Thomas HD, et al.Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase[J]. Nature, 2005, 434(7035): 913-917.
[12] Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy[J]. Nature, 2005, 434(7035): 917-921.
[13] Lord CJ, Ashworth A.PARP inhibitors: synthetic lethality in the clinic[J]. Science, 2017, 355(6330): 1152-1158.
[14] Zimmermann M, Murina O, Reijns MAM, et al.CRISPR screens identify genomic ribonucleotides as a source of PARP-trapping lesions[J]. Nature, 2018, 559(7713): 285-289.
[15] Kim H, Xu H, George E, et al.Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models[J]. Nat Commun, 2020, 11(1): 3726-3742.
[16] Ning JF, Stanciu M, Humphrey MR, et al.Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma[J]. Nat Commun, 2019, 10(1): 2910-2927.
[17] Agrawal N, Frederick MJ, Pickering CR, et al.Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1[J]. Science, 2011, 333(6046): 1154-1157.
[18] Morris LGT, Chandramohan R, West L, et al.The molecular landscape of recurrent and metastatic head and neck cancers: insights from a precision oncology sequencing platform[J]. JAMA Oncol, 2017, 3(2): 244-255.
[19] Deneka AY, Einarson MB, Bennett J, et al.Synthetic lethal targeting of mitotic checkpoints in HPV-negative head and neck cancer[J]. Cancers, 2020, 12(2): 306-323.
[20] Huang M, Feng X, Su D, et al.Genome-wide CRISPR screen uncovers a synergistic effect of combining Haspin and Aurora kinase B inhibition[J]. Oncogene, 2020, 39(21): 4312-4322.
[21] Sambandam V, Frederick MJ, Shen L, et al.PDK1 mediates -mutated head and neck squamous carcinoma vulnerability to therapeutic PI3K/mTOR inhibition[J]. Clin Cancer Res, 2019, 25(11): 3329-3340.
[22] Wang T, Yu H, Hughes NW, et al. Gene essentiality profiling reveals gene networks and synthetic lethal interactions with oncogenic ras [J]. Cell, 2017, 168(5): 890-903.e15.
[23] Chan EM, Shibue T, McFarland JM, et al. WRN helicase is a synthetic lethal target in microsatellite unstable cancers[J]. Nature, 2019, 568(7753): 551-556.
[24] Gong X, Du J, Parsons SH, et al.Aurora A kinase inhibition is synthetic lethal with loss of the tumor suppressor gene[J]. Cancer Discov, 2019, 9(2): 248-263.
[25] Lissanu Deribe Y, Sun Y, Terranova C, et al.Mutations in the SWI/SNF complex induce a targetable dependence on oxidative phosphorylation in lung cancer[J]. Nat Med, 2018, 24(7): 1047-1057.
[26] Biankin AV, Waddell N, Kassahn KS, et al.Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes[J]. Nature, 2012, 491(7424): 399-405.
[27] Szlachta K, Kuscu C, Tufan T, et al.CRISPR knockout screening identifies combinatorial drug targets in pancreatic cancer and models cellular drug response[J]. Nat Commun, 2018, 9(1):4275-4288.
[28] Zaretsky JM, Garcia-Diaz A, Shin DS, et al.Mutations associated with acquired resistance to PD-1 blockade in melanoma[J]. N Engl J Med, 2016, 375(9): 819-829.
[29] Koyama S, Akbay EA, Li YY, et al.STK11/LKB1 Deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment[J]. Cancer Res, 2016, 76(5): 999-1008.
[30] Sade-Feldman M, Jiao YJ, Chen JH, et al.Resistance to checkpoint blockade therapy through inactivation of antigen presentation[J]. Nat Commun, 2017, 8(1): 1136-1147.
[31] Manguso RT, Pope HW, Zimmer MD, et al.In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target[J]. Nature, 2017, 547(7664): 413-418.
[32] Shoemaker RH.The NCI60 human tumour cell line anticancer drug screen[J]. Nat Rev Cancer, 2006, 6(10): 813-823.
[33] Bertotti A, Migliardi G, Galimi F, et al.A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer[J]. Cancer Discov, 2011, 1(6): 508-523.
[34] Xue Z, Vis DJ, Bruna A, et al.MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models[J]. Cell Res, 2018, 28(7): 719-729.
[35] Wang J, Hu K, Guo J, et al.Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK[J]. Nat Commun, 2016, 7: 11363.
[36] Lee J, Kim H, Lee JE, et al. Selective cytotoxicity of the NAMPT inhibitor FK866 toward gastric cancer cells with markers of the epithelial-mesenchymal transition, due to loss of NAPRT [J]. Gastroenterology, 2018, 155(3): 799-814.e13.
[37] McDonald ER, de Weck A, Schlabach MR, et al. Project DRIVE: a compendium of cancer dependencies and synthetic lethal relationships uncovered by large-scale, deep RNAi screening [J]. Cell, 2017, 170(3): 577-592.e10.
[38] Behan FM, Iorio F, Picco G, et al.Prioritization of cancer therapeutic targets using CRISPR-Cas9 screens[J]. Nature, 2019, 568(7753): 511-516.
[39] Aguirre AJ, Meyers RM, Weir BA, et al.Genomic copy number dictates a gene-independent cell response to CRISPR/Cas9 targeting[J]. Cancer Discov, 2016, 6(8):914-929.
[40] Griffith M, Griffith OL, Coffman AC, et al.DGIdb: mining the druggable genome[J]. Nat Methods, 2013, 10(12): 1209-1210.