神经内分泌前列腺癌的研究进展
Research Advances in Neuroendocrine Prostate Cancer
DOI: 10.12677/bp.2025.154031, PDF,   
作者: 刘雪迎, 刘 珂*：山东大学公共卫生学院，山东 济南
关键词: 神经内分泌；前列腺癌；分子靶向治疗；Neuroendocrine； Prostate Cancer； Molecular Targeted Therapy
摘要: 神经内分泌前列腺癌(Neuroendocrine Prostate Cancer, NEPC)是前列腺癌中一类具有高度侵袭性且致死率极高的特殊亚型，其临床特征主要表现为疾病进展迅速、对常规雄激素受体(Androgen Receptor, AR)靶向治疗存在原发性耐药或继发性耐药，且患者预后极差。尽管少数情况下NEPC可原发发生，但更多病例源自前列腺癌在长期接受雄激素剥夺治疗(Androgen Deprivation Therapy, ADT)或雄激素受体通路抑制剂(Androgen Receptor Pathway Inhibitor, ARPI)治疗的压力下，发生转分化而形成。然而，该转分化机制的分子基础迄今仍存在较大争议。NEPC患者整体生存率极低，且目前有效的治疗手段十分有限，其临床管理面临重大挑战。本文系统综述了NEPC的最新研究进展，旨在为NEPC的基础研究转化与临床治疗优化提供参考。
Abstract: Neuroendocrine Prostate Cancer (NEPC) is a rare but highly aggressive subtype of prostate cancer with an exceptionally high mortality rate. Clinically, NEPC is characterized by rapid disease progression, primary resistance or acquired resistance to conventional Androgen Receptor (AR)—targeted therapies, and extremely poor prognosis. Although NEPC can arise de novo in a minority of cases, it more commonly develops through transdifferentiation of prostate adenocarcinoma under the selective pressure of long-term Androgen Deprivation Therapy (ADT) or Androgen Receptor Pathway Inhibitor (ARPI). However, the molecular mechanisms underlying this transdifferentiation remain highly controversial. NEPC patients exhibit very low overall survival, and effective therapeutic options are currently limited, posing major challenges to clinical management. This review provides a comprehensive overview of recent advances in NEPC research, aiming to inform future translational studies and the optimization of clinical treatment strategies.
文章引用：刘雪迎, 刘珂. 神经内分泌前列腺癌的研究进展[J]. 生物过程, 2025, 15(4): 235-244. https://doi.org/10.12677/bp.2025.154031

参考文献

[1] Wang, Y., Wang, Y., Ci, X., Choi, S.Y.C., Crea, F., Lin, D., et al. (2021) Molecular Events in Neuroendocrine Prostate Cancer Development. Nature Reviews Urology, 18, 581-596. [Google Scholar] [CrossRef] [PubMed]
[2] Bluemn, E.G., Coleman, I.M., Lucas, J.M., Coleman, R.T., Hernandez-Lopez, S., Tharakan, R., et al. (2017) Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling. Cancer Cell, 32, 474-489.e6. [Google Scholar] [CrossRef] [PubMed]
[3] Aggarwal, R., Huang, J., Alumkal, J.J., Zhang, L., Feng, F.Y., Thomas, G.V., et al. (2018) Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-Institutional Prospective Study. Journal of Clinical Oncology, 36, 2492-2503. [Google Scholar] [CrossRef] [PubMed]
[4] Demichelis, F., Fall, K., Perner, S., Andrén, O., Schmidt, F., Setlur, S.R., et al. (2007) TMPRSS2:ERG Gene Fusion Associated with Lethal Prostate Cancer in a Watchful Waiting Cohort. Oncogene, 26, 4596-4599. [Google Scholar] [CrossRef] [PubMed]
[5] Rajput, A.B., Miller, M.A., De Luca, A., Boyd, N., Leung, S., Hurtado-Coll, A., et al. (2007) Frequency of the TMPRSS2:ERG Gene Fusion Is Increased in Moderate to Poorly Differentiated Prostate Cancers. Journal of Clinical Pathology, 60, 1238-1243. [Google Scholar] [CrossRef] [PubMed]
[6] Beltran, H., Rickman, D.S., Park, K., Chae, S.S., Sboner, A., MacDonald, T.Y., et al. (2011) Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of New Drug Targets. Cancer Discovery, 1, 487-495. [Google Scholar] [CrossRef] [PubMed]
[7] Zou, M., Toivanen, R., Mitrofanova, A., Floch, N., Hayati, S., Sun, Y., et al. (2017) Transdifferentiation as a Mechanism of Treatment Resistance in a Mouse Model of Castration-Resistant Prostate Cancer. Cancer Discovery, 7, 736-749. [Google Scholar] [CrossRef] [PubMed]
[8] Tan, H., Sood, A., Rahimi, H.A., Wang, W., Gupta, N., Hicks, J., et al. (2014) Rb Loss Is Characteristic of Prostatic Small Cell Neuroendocrine Carcinoma. Clinical Cancer Research, 20, 890-903. [Google Scholar] [CrossRef] [PubMed]
[9] Kaye, F.J. (2002) RB and Cyclin Dependent Kinase Pathways: Defining a Distinction between RB and P16 Loss in Lung Cancer. Oncogene, 21, 6908-6914. [Google Scholar] [CrossRef] [PubMed]
[10] Tsai, H., Morais, C.L., Alshalalfa, M., Tan, H., Haddad, Z., Hicks, J., et al. (2015) Cyclin D1 Loss Distinguishes Prostatic Small-Cell Carcinoma from Most Prostatic Adenocarcinomas. Clinical Cancer Research, 21, 5619-5629. [Google Scholar] [CrossRef] [PubMed]
[11] Ku, S.Y., Rosario, S., Wang, Y., Mu, P., Seshadri, M., Goodrich, Z.W., et al. (2017) Rb1 and Trp53 Cooperate to Suppress Prostate Cancer Lineage Plasticity, Metastasis, and Antiandrogen Resistance. Science, 355, 78-83. [Google Scholar] [CrossRef] [PubMed]
[12] Mu, P., Zhang, Z., Benelli, M., Karthaus, W.R., Hoover, E., Chen, C., et al. (2017) SOX2 Promotes Lineage Plasticity and Antiandrogen Resistance in TP53-and RB1-Deficient Prostate Cancer. Science, 355, 84-88. [Google Scholar] [CrossRef] [PubMed]
[13] Chen, R., Dong, X. and Gleave, M. (2018) Molecular Model for Neuroendocrine Prostate Cancer Progression. BJU International, 122, 560-570. [Google Scholar] [CrossRef] [PubMed]
[14] Ge, R., Wang, Z., Montironi, R., Jiang, Z., Cheng, M., Santoni, M., et al. (2020) Epigenetic Modulations and Lineage Plasticity in Advanced Prostate Cancer. Annals of Oncology, 31, 470-479. [Google Scholar] [CrossRef] [PubMed]
[15] Beltran, H., Prandi, D., Mosquera, J.M., Benelli, M., Puca, L., Cyrta, J., et al. (2016) Divergent Clonal Evolution of Castration-Resistant Neuroendocrine Prostate Cancer. Nature Medicine, 22, 298-305. [Google Scholar] [CrossRef] [PubMed]
[16] Beltran, H., Romanel, A., Conteduca, V., Casiraghi, N., Sigouros, M., Franceschini, G.M., et al. (2020) Circulating Tumor DNA Profile Recognizes Transformation to Castration-Resistant Neuroendocrine Prostate Cancer. Journal of Clinical Investigation, 130, 1653-1668. [Google Scholar] [CrossRef] [PubMed]
[17] Lee, T.I., Jenner, R.G., Boyer, L.A., Guenther, M.G., Levine, S.S., Kumar, R.M., et al. (2006) Control of Developmental Regulators by Polycomb in Human Embryonic Stem Cells. Cell, 125, 301-313. [Google Scholar] [CrossRef] [PubMed]
[18] Zhang, Y., Zheng, D., Zhou, T., Song, H., Hulsurkar, M., Su, N., et al. (2018) Androgen Deprivation Promotes Neuroendocrine Differentiation and Angiogenesis through CREB-EZH2-TSP1 Pathway in Prostate Cancers. Nature Communications, 9, Article No. 4080. [Google Scholar] [CrossRef] [PubMed]
[19] Kleb, B., Estécio, M.R.H., Zhang, J., Tzelepi, V., Chung, W., Jelinek, J., et al. (2016) Differentially Methylated Genes and Androgen Receptor Re-Expression in Small Cell Prostate Carcinomas. Epigenetics, 11, 184-193. [Google Scholar] [CrossRef] [PubMed]
[20] Lapuk, A.V., Wu, C., Wyatt, A.W., McPherson, A., McConeghy, B.J., Brahmbhatt, S., et al. (2012) From Sequence to Molecular Pathology, and a Mechanism Driving the Neuroendocrine Phenotype in Prostate Cancer. The Journal of Pathology, 227, 286-297. [Google Scholar] [CrossRef] [PubMed]
[21] Zhang, X., Coleman, I.M., Brown, L.G., True, L.D., Kollath, L., Lucas, J.M., et al. (2015) SRRM4 Expression and the Loss of REST Activity May Promote the Emergence of the Neuroendocrine Phenotype in Castration-Resistant Prostate Cancer. Clinical Cancer Research, 21, 4698-4708. [Google Scholar] [CrossRef] [PubMed]
[22] Terry, S. and Beltran, H. (2014) The Many Faces of Neuroendocrine Differentiation in Prostate Cancer Progression. Frontiers in Oncology, 4, Article 60. [Google Scholar] [CrossRef] [PubMed]
[23] Svensson, C., Ceder, J., Iglesias-Gato, D., Chuan, Y., Pang, S.T., Bjartell, A., et al. (2013) REST Mediates Androgen Receptor Actions on Gene Repression and Predicts Early Recurrence of Prostate Cancer. Nucleic Acids Research, 42, 999-1015. [Google Scholar] [CrossRef] [PubMed]
[24] Panman, L., Andersson, E., Alekseenko, Z., Hedlund, E., Kee, N., Mong, J., et al. (2011) Transcription Factor-Induced Lineage Selection of Stem-Cell-Derived Neural Progenitor Cells. Cell Stem Cell, 8, 663-675. [Google Scholar] [CrossRef] [PubMed]
[25] Ramnarine, V.R., Alshalalfa, M., Mo, F., Nabavi, N., Erho, N., Takhar, M., et al. (2018) The Long Noncoding RNA Landscape of Neuroendocrine Prostate Cancer and Its Clinical Implications. GigaScience, 7, giy050. [Google Scholar] [CrossRef] [PubMed]
[26] Crea, F., Venalainen, E., Ci, X., Cheng, H., Pikor, L., Parolia, A., et al. (2016) The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer. Epigenomics, 8, 721-731. [Google Scholar] [CrossRef] [PubMed]
[27] Guo, H., Ci, X., Ahmed, M., Hua, J.T., Soares, F., Lin, D., et al. (2019) ONECUT2 Is a Driver of Neuroendocrine Prostate Cancer. Nature Communications, 10, Article No. 278. [Google Scholar] [CrossRef] [PubMed]
[28] Rotinen, M., You, S., Yang, J., Coetzee, S.G., Reis-Sobreiro, M., Huang, W., et al. (2018) ONECUT2 Is a Targetable Master Regulator of Lethal Prostate Cancer That Suppresses the Androgen Axis. Nature Medicine, 24, 1887-1898. [Google Scholar] [CrossRef] [PubMed]
[29] Zaffuto, E., Pompe, R., Zanaty, M., Bondarenko, H.D., Leyh-Bannurah, S., Moschini, M., et al. (2017) Contemporary Incidence and Cancer Control Outcomes of Primary Neuroendocrine Prostate Cancer: A SEER Database Analysis. Clinical Genitourinary Cancer, 15, e793-e800. [Google Scholar] [CrossRef] [PubMed]
[30] Vlachostergios, P.J., Puca, L. and Beltran, H. (2017) Emerging Variants of Castration-Resistant Prostate Cancer. Current Oncology Reports, 19, Article No. 32. [Google Scholar] [CrossRef] [PubMed]
[31] Abida, W., Cyrta, J., Heller, G., Prandi, D., Armenia, J., Coleman, I., et al. (2019) Genomic Correlates of Clinical Outcome in Advanced Prostate Cancer. Proceedings of the National Academy of Sciences of the United States of America, 116, 11428-11436. [Google Scholar] [CrossRef] [PubMed]
[32] Zamora, I., Freeman, M.R., Encío, I.J. and Rotinen, M. (2023) Targeting Key Players of Neuroendocrine Differentiation in Prostate Cancer. International Journal of Molecular Sciences, 24, 13673. [Google Scholar] [CrossRef] [PubMed]
[33] Epstein, J.I., Amin, M.B., Beltran, H., Lotan, T.L., Mosquera, J., Reuter, V.E., et al. (2014) Proposed Morphologic Classification of Prostate Cancer with Neuroendocrine Differentiation. American Journal of Surgical Pathology, 38, 756-767. [Google Scholar] [CrossRef] [PubMed]
[34] Conteduca, V., Oromendia, C., Eng, K.W., Bareja, R., Sigouros, M., Molina, A., et al. (2019) Clinical Features of Neuroendocrine Prostate Cancer. European Journal of Cancer, 121, 7-18. [Google Scholar] [CrossRef] [PubMed]
[35] Okasho, K., Ogawa, O. and Akamatsu, S. (2021) Narrative Review of Challenges in the Management of Advanced Neuroendocrine Prostate Cancer. Translational Andrology and Urology, 10, 3953-3962. [Google Scholar] [CrossRef] [PubMed]
[36] Aggarwal, R., Zhang, T., Small, E.J. and Armstrong, A.J. (2014) Neuroendocrine Prostate Cancer: Subtypes, Biology, and Clinical Outcomes. Journal of the National Comprehensive Cancer Network, 12, 719-726. [Google Scholar] [CrossRef] [PubMed]
[37] Fine, S.W. (2018) Neuroendocrine Tumors of the Prostate. Modern Pathology, 31, 122-132. [Google Scholar] [CrossRef] [PubMed]
[38] Formaggio, N., Rubin, M.A. and Theurillat, J. (2021) Loss and Revival of Androgen Receptor Signaling in Advanced Prostate Cancer. Oncogene, 40, 1205-1216. [Google Scholar] [CrossRef] [PubMed]
[39] Spetsieris, N., Boukovala, M., Patsakis, G., Alafis, I. and Efstathiou, E. (2020) Neuroendocrine and Aggressive-Variant Prostate Cancer. Cancers, 12, Article 3792. [Google Scholar] [CrossRef] [PubMed]
[40] Hu, J., Han, B. and Huang, J. (2019) Morphologic Spectrum of Neuroendocrine Tumors of the Prostate: An Updated Review. Archives of Pathology & Laboratory Medicine, 144, 320-325. [Google Scholar] [CrossRef] [PubMed]
[41] Butler, W. and Huang, J. (2021) Neuroendocrine Cells of the Prostate: Histology, Biological Functions, and Molecular Mechanisms. Precision Clinical Medicine, 4, 25-34. [Google Scholar] [CrossRef] [PubMed]
[42] Tsai, H.K., Lehrer, J., Alshalalfa, M., Erho, N., Davicioni, E. and Lotan, T.L. (2017) Gene Expression Signatures of Neuroendocrine Prostate Cancer and Primary Small Cell Prostatic Carcinoma. BMC Cancer, 17, Article No. 759. [Google Scholar] [CrossRef] [PubMed]
[43] Abdulfatah, E., Fine, S.W., Lotan, T.L. and Mehra, R. (2022) De Novo Neuroendocrine Features in Prostate Cancer. Human Pathology, 127, 112-122. [Google Scholar] [CrossRef] [PubMed]
[44] Haffner, M.C., Morris, M.J., Ding, C.C., Sayar, E., Mehra, R., Robinson, B., et al. (2024) Framework for the Pathology Workup of Metastatic Castration-Resistant Prostate Cancer Biopsies. Clinical Cancer Research, 31, 466-478. [Google Scholar] [CrossRef] [PubMed]
[45] Gupta, S., Vanderbilt, C., Abida, W., Fine, S.W., Tickoo, S.K., Al-Ahmadie, H.A., et al. (2020) Immunohistochemistry-based Assessment of Androgen Receptor Status and the AR-Null Phenotype in Metastatic Castrate Resistant Prostate Cancer. Prostate Cancer and Prostatic Diseases, 23, 507-516. [Google Scholar] [CrossRef] [PubMed]
[46] Tagawa, S.T. (2014) Neuroendocrine Prostate Cancer after Hormonal Therapy: Knowing Is Half the Battle. Journal of Clinical Oncology, 32, 3360-3364. [Google Scholar] [CrossRef] [PubMed]
[47] Beltran, H., Tomlins, S., Aparicio, A., Arora, V., Rickman, D., Ayala, G., et al. (2014) Aggressive Variants of Castration-Resistant Prostate Cancer. Clinical Cancer Research, 20, 2846-2850. [Google Scholar] [CrossRef] [PubMed]
[48] Aparicio, A.M., Harzstark, A.L., Corn, P.G., Wen, S., Araujo, J.C., Tu, S., et al. (2013) Platinum-Based Chemotherapy for Variant Castrate-Resistant Prostate Cancer. Clinical Cancer Research, 19, 3621-3630. [Google Scholar] [CrossRef] [PubMed]
[49] Amato, R.J., Logothetis, C.J., Hallinan, R., Ro, J.Y., Sella, A. and Dexeus, F.H. (1992) Chemotherapy for Small Cell Carcinoma of Prostatic Origin. Journal of Urology, 147, 935-937. [Google Scholar] [CrossRef] [PubMed]
[50] Dasari, S. and Bernard Tchounwou, P. (2014) Cisplatin in Cancer Therapy: Molecular Mechanisms of Action. European Journal of Pharmacology, 740, 364-378. [Google Scholar] [CrossRef] [PubMed]
[51] Montecucco, A., Zanetta, F. and Biamonti, G. (2015) Molecular Mechanisms of Etoposide. EXCLI Journal, 14, 95-108.
[52] Chang, H., Moudgil, R., Scarabelli, T., Okwuosa, T.M. and Yeh, E.T.H. (2017) Cardiovascular Complications of Cancer Therapy: Best Practices in Diagnosis, Prevention, and Management: Part 1. Journal of the American College of Cardiology, 70, 2536-2551. [Google Scholar] [CrossRef] [PubMed]
[53] Corn, P.G., Heath, E.I., Zurita, A., Ramesh, N., Xiao, L., Sei, E., et al. (2019) Cabazitaxel Plus Carboplatin for the Treatment of Men with Metastatic Castration-Resistant Prostate Cancers: A Randomised, Open-Label, Phase 1-2 Trial. The Lancet Oncology, 20, 1432-1443. [Google Scholar] [CrossRef] [PubMed]
[54] Sehrawat, A., Gao, L., Wang, Y., Bankhead, A., McWeeney, S.K., King, C.J., et al. (2018) LSD1 Activates a Lethal Prostate Cancer Gene Network Independently of Its Demethylase Function. Proceedings of the National Academy of Sciences of the United States of America, 115, E4179-E4188. [Google Scholar] [CrossRef] [PubMed]
[55] Stewart, C.A. and Byers, L.A. (2015) Altering the Course of Small Cell Lung Cancer: Targeting Cancer Stem Cells via LSD1 Inhibition. Cancer Cell, 28, 4-6. [Google Scholar] [CrossRef] [PubMed]
[56] Beltran, H., Oromendia, C., Danila, D.C., Montgomery, B., Hoimes, C., Szmulewitz, R.Z., et al. (2019) A Phase II Trial of the Aurora Kinase a Inhibitor Alisertib for Patients with Castration-Resistant and Neuroendocrine Prostate Cancer: Efficacy and Biomarkers. Clinical Cancer Research, 25, 43-51. [Google Scholar] [CrossRef] [PubMed]
[57] Bellmunt, J., de Wit, R., Vaughn, D.J., Fradet, Y., Lee, J., Fong, L., et al. (2017) Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma. New England Journal of Medicine, 376, 1015-1026. [Google Scholar] [CrossRef] [PubMed]
[58] Balar, A.V., Castellano, D., O'Donnell, P.H., Grivas, P., Vuky, J., Powles, T., et al. (2017) First-line Pembrolizumab in Cisplatin-Ineligible Patients with Locally Advanced and Unresectable or Metastatic Urothelial Cancer (KEYNOTE-052): A Multicentre, Single-Arm, Phase 2 Study. The Lancet Oncology, 18, 1483-1492. [Google Scholar] [CrossRef] [PubMed]
[59] Sharma, P., Retz, M., Siefker-Radtke, A., Baron, A., Necchi, A., Bedke, J., et al. (2017) Nivolumab in Metastatic Urothelial Carcinoma after Platinum Therapy (Checkmate 275): A Multicentre, Single-Arm, Phase 2 Trial. The Lancet Oncology, 18, 312-322. [Google Scholar] [CrossRef] [PubMed]
[60] Pasero, C., Gravis, G., Guerin, M., Granjeaud, S., Thomassin-Piana, J., Rocchi, P., et al. (2016) Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity. Cancer Research, 76, 2153-2165. [Google Scholar] [CrossRef] [PubMed]
[61] Ciavarra, R.P., Holterman, D.A., Brown, R.R., Mangiotti, P., Yousefieh, N., Wright, G.L., et al. (2004) Prostate Tumor Microenvironment Alters Immune Cells and Prevents Long-Term Survival in an Orthotopic Mouse Model Following Flt3-Ligand/CD40-Ligand Immunotherapy. Journal of Immunotherapy, 27, 13-26. [Google Scholar] [CrossRef] [PubMed]
[62] Beer, T.M., Kwon, E.D., Drake, C.G., Fizazi, K., Logothetis, C., Gravis, G., et al. (2017) Randomized, Double-Blind, Phase III Trial of Ipilimumab versus Placebo in Asymptomatic or Minimally Symptomatic Patients with Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. Journal of Clinical Oncology, 35, 40-47. [Google Scholar] [CrossRef] [PubMed]
[63] Topalian, S.L., Hodi, F.S., Brahmer, J.R., Gettinger, S.N., Smith, D.C., McDermott, D.F., et al. (2012) Safety, Activity, and Immune Correlates of Anti-PD-1 Antibody in Cancer. New England Journal of Medicine, 366, 2443-2454. [Google Scholar] [CrossRef] [PubMed]
[64] Antonarakis, E.S., Piulats, J.M., Gross-Goupil, M., Goh, J., Ojamaa, K., Hoimes, C.J., et al. (2020) Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. Journal of Clinical Oncology, 38, 395-405. [Google Scholar] [CrossRef] [PubMed]
[65] Rickman, D.S., Beltran, H., Demichelis, F. and Rubin, M.A. (2017) Biology and Evolution of Poorly Differentiated Neuroendocrine Tumors. Nature Medicine, 23, 664-673. [Google Scholar] [CrossRef] [PubMed]
[66] Alexandrov, L.B., Ju, Y.S., Haase, K., Van Loo, P., Martincorena, I., Nik-Zainal, S., et al. (2016) Mutational Signatures Associated with Tobacco Smoking in Human Cancer. Science, 354, 618-622. [Google Scholar] [CrossRef] [PubMed]
[67] Horn, L., Mansfield, A.S., Szczęsna, A., Havel, L., Krzakowski, M., Hochmair, M.J., et al. (2018) First-Line Atezolizumab Plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. New England Journal of Medicine, 379, 2220-2229. [Google Scholar] [CrossRef] [PubMed]
[68] Vicier, C., Xie, W., Hamid, A., Evan, C. and Sweeney, C. (2019) Impact of New Systemic Therapies on Outcomes of Patients with Non-Metastatic Castration Resistant Prostate Cancer (nmCRPC). Journal of Clinical Oncology, 37, 244-244. [Google Scholar] [CrossRef] 
[69] Nappi, L., Kesch, C., Vahid, S., Fazli, L., Eigl, B.J., Kollmannsberger, C.K., et al. (2019) Immunogenomic Landscape of Neuroendocrine Small Cell Prostate Cancer. Journal of Clinical Oncology, 37, 217-217. [Google Scholar] [CrossRef] 
[70] Jin, H., Shi, Y., Lv, Y., Yuan, S., Ramirez, C.F.A., Lieftink, C., et al. (2021) EGFR Activation Limits the Response of Liver Cancer to Lenvatinib. Nature, 595, 730-734. [Google Scholar] [CrossRef] [PubMed]
[71] Liu, B., Li, L., Yang, G., Geng, C., Luo, Y., Wu, W., et al. (2019) PARP Inhibition Suppresses GR-MYCN-CDK5-RB1-E2F1 Signaling and Neuroendocrine Differentiation in Castration-Resistant Prostate Cancer. Clinical Cancer Research, 25, 6839-6851. [Google Scholar] [CrossRef] [PubMed]
[72] Kooshkaki, O., Derakhshani, A., Hosseinkhani, N., Torabi, M., Safaei, S., Brunetti, O., et al. (2020) Combination of Ipilimumab and Nivolumab in Cancers: From Clinical Practice to Ongoing Clinical Trials. International Journal of Molecular Sciences, 21, Article 4427. [Google Scholar] [CrossRef] [PubMed]
[73] Mansfield, A.S., Hong, D.S., Hann, C.L., Farago, A.F., Beltran, H., Waqar, S.N., et al. (2021) A Phase I/II Study of Rovalpituzumab Tesirine in Delta-Like 3—Expressing Advanced Solid Tumors. npj Precision Oncology, 5, Article No. 74. [Google Scholar] [CrossRef] [PubMed]
[74] Isobe, Y., Sato, K., Nishinaga, Y., Takahashi, K., Taki, S., Yasui, H., et al. (2020) Near Infrared Photoimmunotherapy Targeting DLL3 for Small Cell Lung Cancer. EBioMedicine, 52, Article ID: 102632. [Google Scholar] [CrossRef] [PubMed]
[75] Giffin, M.J., Cooke, K., Lobenhofer, E.K., Estrada, J., Zhan, J., Deegen, P., et al. (2021) AMG 757, a Half-Life Extended, Dll3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer. Clinical Cancer Research, 27, 1526-1537. [Google Scholar] [CrossRef] [PubMed]