协同致死效应在肿瘤研究中的现状
|
摘要
包括导致基因功能缺失在内的大部分致癌突变均不是传统的小分子抑制剂的直接作用靶点。尽管对致癌相关突变的了解越来越多,但目前肿瘤的靶向治疗依然存在问题,协同致死效应(synthetic lethality effects)的应用有望成为肿瘤靶向治疗中的新突破。因此,寻找能够产生协同致死效应的基因突变组合对于肿瘤靶向治疗有着重大的作用,本文就协同致死效应概念的提出与演变、相互作用形式、相关筛选技术以及临床治疗策略、意义和挑战等方面进行综述。
Most carcinogenic mutations, including those causing a loss of function, are not directly "druggable" with traditional smallmolecule inhibitors, such as targeted drugs. Thus, despite our growing cognition of carcinogenic mutations that drive tumor progression, there are still problems regarding targeted therapy for tumors. The application of synthetic lethality effects is expected to become a new breakthrough in tumor-targeted therapy. Therefore, identifying a combination of genetic mutations that generate synthetic lethality effects plays important roles in targeted therapy for tumors. This article reviews the origin and development of synthetic lethality effects, the forms of interaction, related screening techniques, clinical treatment strategies, and significance and challenges.
Most carcinogenic mutations, including those causing a loss of function, are not directly "druggable" with traditional smallmolecule inhibitors, such as targeted drugs. Thus, despite our growing cognition of carcinogenic mutations that drive tumor progression, there are still problems regarding targeted therapy for tumors. The application of synthetic lethality effects is expected to become a new breakthrough in tumor-targeted therapy. Therefore, identifying a combination of genetic mutations that generate synthetic lethality effects plays important roles in targeted therapy for tumors. This article reviews the origin and development of synthetic lethality effects, the forms of interaction, related screening techniques, clinical treatment strategies, and significance and challenges.
引文
[1] Apaolaza I, San José-Eneriz E, Tobalina L, et al. An in-silico approach to predict and exploit synthetic lethality in cancer metabolism[J]. Nat Commun, 2017, 8(1):459.
[2] Laskin J, Jones S, Aparicio S, et al. Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers[J]. Cold Spring Harb Mol Case Stud, 2015, 1(1):a000570.
[3] O'Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer[J]. Nat Rev Genet, 2017, 18(10):613-623.
[4] Swanton C, Soria JC, Bardelli A, et al. Consensus on precision medicine for metastatic cancers:a report from the MAP conference[J]. Ann Oncol, 2016, 27(8):1443-1448.
[5] Lategahn J, Keul M, Rauh D. Lessons to be learned:the molecular basis of kinase-targeted therapies and drug resistance in non-small cell lung cancer[J]. Angew Chem Int Ed Engl, 2018, 57(9):2307-2313.
[6] Hartwell LH, Szankasi P, Roberts CJ, et al. Integrating genetic approaches into the discovery of anticancer drugs[J]. Science, 1997, 278(5340):1064-1068.
[7] 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.
[8] Farmer H, Mc Cabe 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.
[9] Li S. Inhibition of poly(ADP-ribose)polymerase in BRCA mutation carriers[J]. N Engl J Med, 2009, 361(17):1707.
[10] Xie L, Gazin C, Park SM, et al. A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in p53-deficient human cancer cells[J]. PLoS Genet, 2012, 8(12):e1003151.
[11] Sinha S, Thomas D, Chan S, et al. Systematic discovery of mutationspecific synthetic lethals by mining pan-cancer human primary tumor data[J]. Nat Commun, 2017, 8:15580.
[12] Williams SP, Barthorpe AS, Lightfoot H, et al. High-throughput RNAi screen for essential genes and drug synergistic combinations in colorectal cancer[J]. Sci Data, 2017, 4:170139.
[13] Fan Y, Arechederra M, Richelme S, et al. A phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of nononcogenic receptor tyrosine kinases[J]. Hepatology, 2017,66(5):1644-1661.
[14] Williamson CT, Miller R, Pemberton HN, et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A[J]. Nat Commun, 2016, 7:13837.
[15] Azzariti A, Mancarella S, Porcelli L, et al. Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin-332/α3 integrin axis recovery of focal adhesion kinase ubiquitination[J]. Hepatology, 2016, 64(6):2103-2117.
[16] Zack TI, Schumacher SE, Carter SL, et al. Pan-cancer patterns of somatic copy number alteration[J]. Nat Genet, 2013, 45(10):1134-1140.
[17] Yan H, Gibson S, Tye BK. Mcm2 and Mcm3, two proteins important for ARS activity, are related in structure and function[J]. Genes Dev, 1991,5(6):944-957.
[18] Kroll ES, Hyland KM, Hieter P, et al. Establishing genetic interactions by a synthetic dosage lethality phenotype[J]. Genetics, 1996, 143(1):95-102.
[19] Bian Y, Kitagawa R, Bansal PK, et al. Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors[J]. Proc Natl Acad Sci U S A, 2014, 111(4):1628-1633.
[20] Reid RJ, Du X, Sunjevaric I, et al. A synthetic dosage lethal genetic interaction between cks1b and plk1 is conserved in yeast and human cancer cells[J]. Genetics, 2016, 204(2):807-819.
[21] Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies[J]. Nat Rev Clin Oncol, 2018, 15(2):81-94.
[22] Tong AH, Lesage G, Bader GD, et al. Global mapping of the yeast genetic interaction network[J]. Science, 2004, 303(5659):808-813.
[23] Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans[J].Nature, 1998, 391(6669):806-811.
[24] Paddison PJ, Caudy AA, Bernstein E, et al. Short hairpin RNAs(sh RNAs)induce sequence-specific silencing in mammalian cells[J]. Genes Dev,2002, 16(8):948-958.
[25] addison PJ, Silva JM, Conklin DS, et al. A resource for large-scale RNAinterference-based screens in mammals[J]. Nature, 2004, 428(6981):427-431.
[26] Bou Samra E, Buhagiar-Labarchède G, Machon C, et al. A role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminasedeficient cell survival[J]. Nat Commun, 2017, 8(1):693.
[27] 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.
[28] Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems[J]. Science, 2013, 339(6121):819-823.
[29] Hart T, Chandrashekhar M, Aregger M, et al. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities[J].Cell, 2015, 163(6):1515-1526.
[30] Shi J, Wang E, Milazzo JP, et al. Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains[J]. Nat Biotechnol, 2015,33(6):661-667.
[31] Leiserson MD, Wu HT, Vandin F, et al. Erratum to:Co MEt:a statistical approach to identify combinations of mutually exclusive alterations in cancer[J]. Genome Biol, 2016, 17(1):168.
[32] Jerby-Arnon L, Pfetzer N, Waldman YY, et al. Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality[J]. Cell,2014,158(5):1199-1209.
[33] Jackson RA, Chen ES. Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs[J]. Pharmacol Ther,2016, 162:69-85.
[34] Smida M, Fece de la Cruz F, Kerzendorfer C, et al. MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated[J]. Nat Commun, 2016, 7:13701.
[35] Kedves AT, Gleim S, Liang X, et al. Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C[J]. J Clin Invest, 2017, 127(12):4554-4568.
[36] Ning J, Wakimoto H, Peters C, et al. Rad51 degradation:role in oncolytic virus-poly(adp-ribose)polymerase inhibitor combination therapy in glioblastoma[J]. J Natl Cancer Inst, 2017, 109(3):1-13.
[37] Chen B, Ma L, Paik H, et al. Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets[J]. Nat Commun, 2017, 8:16022.
[2] Laskin J, Jones S, Aparicio S, et al. Lessons learned from the application of whole-genome analysis to the treatment of patients with advanced cancers[J]. Cold Spring Harb Mol Case Stud, 2015, 1(1):a000570.
[3] O'Neil NJ, Bailey ML, Hieter P. Synthetic lethality and cancer[J]. Nat Rev Genet, 2017, 18(10):613-623.
[4] Swanton C, Soria JC, Bardelli A, et al. Consensus on precision medicine for metastatic cancers:a report from the MAP conference[J]. Ann Oncol, 2016, 27(8):1443-1448.
[5] Lategahn J, Keul M, Rauh D. Lessons to be learned:the molecular basis of kinase-targeted therapies and drug resistance in non-small cell lung cancer[J]. Angew Chem Int Ed Engl, 2018, 57(9):2307-2313.
[6] Hartwell LH, Szankasi P, Roberts CJ, et al. Integrating genetic approaches into the discovery of anticancer drugs[J]. Science, 1997, 278(5340):1064-1068.
[7] 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.
[8] Farmer H, Mc Cabe 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.
[9] Li S. Inhibition of poly(ADP-ribose)polymerase in BRCA mutation carriers[J]. N Engl J Med, 2009, 361(17):1707.
[10] Xie L, Gazin C, Park SM, et al. A synthetic interaction screen identifies factors selectively required for proliferation and TERT transcription in p53-deficient human cancer cells[J]. PLoS Genet, 2012, 8(12):e1003151.
[11] Sinha S, Thomas D, Chan S, et al. Systematic discovery of mutationspecific synthetic lethals by mining pan-cancer human primary tumor data[J]. Nat Commun, 2017, 8:15580.
[12] Williams SP, Barthorpe AS, Lightfoot H, et al. High-throughput RNAi screen for essential genes and drug synergistic combinations in colorectal cancer[J]. Sci Data, 2017, 4:170139.
[13] Fan Y, Arechederra M, Richelme S, et al. A phosphokinome-based screen uncovers new drug synergies for cancer driven by liver-specific gain of nononcogenic receptor tyrosine kinases[J]. Hepatology, 2017,66(5):1644-1661.
[14] Williamson CT, Miller R, Pemberton HN, et al. ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A[J]. Nat Commun, 2016, 7:13837.
[15] Azzariti A, Mancarella S, Porcelli L, et al. Hepatic stellate cells induce hepatocellular carcinoma cell resistance to sorafenib through the laminin-332/α3 integrin axis recovery of focal adhesion kinase ubiquitination[J]. Hepatology, 2016, 64(6):2103-2117.
[16] Zack TI, Schumacher SE, Carter SL, et al. Pan-cancer patterns of somatic copy number alteration[J]. Nat Genet, 2013, 45(10):1134-1140.
[17] Yan H, Gibson S, Tye BK. Mcm2 and Mcm3, two proteins important for ARS activity, are related in structure and function[J]. Genes Dev, 1991,5(6):944-957.
[18] Kroll ES, Hyland KM, Hieter P, et al. Establishing genetic interactions by a synthetic dosage lethality phenotype[J]. Genetics, 1996, 143(1):95-102.
[19] Bian Y, Kitagawa R, Bansal PK, et al. Synthetic genetic array screen identifies PP2A as a therapeutic target in Mad2-overexpressing tumors[J]. Proc Natl Acad Sci U S A, 2014, 111(4):1628-1633.
[20] Reid RJ, Du X, Sunjevaric I, et al. A synthetic dosage lethal genetic interaction between cks1b and plk1 is conserved in yeast and human cancer cells[J]. Genetics, 2016, 204(2):807-819.
[21] Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies[J]. Nat Rev Clin Oncol, 2018, 15(2):81-94.
[22] Tong AH, Lesage G, Bader GD, et al. Global mapping of the yeast genetic interaction network[J]. Science, 2004, 303(5659):808-813.
[23] Fire A, Xu S, Montgomery MK, et al. Potent and specific genetic interference by double-stranded RNA in caenorhabditis elegans[J].Nature, 1998, 391(6669):806-811.
[24] Paddison PJ, Caudy AA, Bernstein E, et al. Short hairpin RNAs(sh RNAs)induce sequence-specific silencing in mammalian cells[J]. Genes Dev,2002, 16(8):948-958.
[25] addison PJ, Silva JM, Conklin DS, et al. A resource for large-scale RNAinterference-based screens in mammals[J]. Nature, 2004, 428(6981):427-431.
[26] Bou Samra E, Buhagiar-Labarchède G, Machon C, et al. A role for Tau protein in maintaining ribosomal DNA stability and cytidine deaminasedeficient cell survival[J]. Nat Commun, 2017, 8(1):693.
[27] 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.
[28] Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems[J]. Science, 2013, 339(6121):819-823.
[29] Hart T, Chandrashekhar M, Aregger M, et al. High-resolution CRISPR screens reveal fitness genes and genotype-specific cancer liabilities[J].Cell, 2015, 163(6):1515-1526.
[30] Shi J, Wang E, Milazzo JP, et al. Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains[J]. Nat Biotechnol, 2015,33(6):661-667.
[31] Leiserson MD, Wu HT, Vandin F, et al. Erratum to:Co MEt:a statistical approach to identify combinations of mutually exclusive alterations in cancer[J]. Genome Biol, 2016, 17(1):168.
[32] Jerby-Arnon L, Pfetzer N, Waldman YY, et al. Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality[J]. Cell,2014,158(5):1199-1209.
[33] Jackson RA, Chen ES. Synthetic lethal approaches for assessing combinatorial efficacy of chemotherapeutic drugs[J]. Pharmacol Ther,2016, 162:69-85.
[34] Smida M, Fece de la Cruz F, Kerzendorfer C, et al. MEK inhibitors block growth of lung tumours with mutations in ataxia-telangiectasia mutated[J]. Nat Commun, 2016, 7:13701.
[35] Kedves AT, Gleim S, Liang X, et al. Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C[J]. J Clin Invest, 2017, 127(12):4554-4568.
[36] Ning J, Wakimoto H, Peters C, et al. Rad51 degradation:role in oncolytic virus-poly(adp-ribose)polymerase inhibitor combination therapy in glioblastoma[J]. J Natl Cancer Inst, 2017, 109(3):1-13.
[37] Chen B, Ma L, Paik H, et al. Reversal of cancer gene expression correlates with drug efficacy and reveals therapeutic targets[J]. Nat Commun, 2017, 8:16022.