Targeted inhibition of the WEE1 kinase as a novel therapeutic strategy in neuroendocrine neoplasms

in Endocrine-Related Cancer
View More View Less
  • 1 Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
  • | 2 Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
  • | 3 Deutsches Zentrum Immuntherapie DZI, Erlangen, Germany
  • | 4 Comprehensive Cancer Center CCC-EMN, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany

Correspondence should be addressed to M Pavel: marianne.pavel@uk-erlangen.de
Restricted access

Neuroendocrine neoplasms (NENs) represent a rare and heterogeneous group of malignancies, sharing features of both neural and endocrine cells. NENs G3 appear as a highly aggressive subset with a poor prognosis and limited therapeutic options. The small-molecule inhibitor of the WEE1 tyrosine kinase, adavosertib (AZD1775), has previously demonstrated potent anti-tumor effects on various types of cancer in preclinical and clinical studies. However, the role of adavosertib in NENs G3 had remained elusive. We evaluated the effects of adavosertib on pancreatic (BON-1, QGP-1) and bronchopulmonary (NCI-H720) neuroendocrine tumor cell lines applying 2D and 3D spheroid models. We newly demonstrated that adavosertib is sufficient to reduce cell viability and proliferation in neuroendocrine cell lines with features of high-grade NENs. As underlying mechanisms, we identified adavosertib-mediated DNA double-strand breaks and a G2/M cell cycle checkpoint abrogation leading into mitotic catastrophe and cancer cell apoptosis. Silencing of WEE1 via siRNA transfection resulted in a phenotype similar to adavosertib treatment. Together, inhibition of the WEE1 tyrosine kinase applying adavosertib on NENs G3 outlines a promising novel therapeutic strategy.

Supplementary Materials

    • SUPPLEMENTARY FIGURE 1 Characterization of Ki-67 index in BON-1 and NCI-H720 cell lines. (A) Immunofluorescence staining of BON-1 cells for Ki-67 (red). Nuclei were counterstained with DAPI (blue). Representative image is shown as a z-stack. Image acquisition was performed with a confocal microscope at 40x magnification. For Ki-67 index ten images per experiment were quantified and percentage Ki-67+ cells/cell count was calculated. Four independent experiments were performed. (B) Flow cytometry of NCI-H720 cells for Ki-67. The percentage of Ki-67+ fraction was measured with MACSQuant16 and analyzed via FlowJo. A representative flow cytometry plot is shown. For Ki-67 index three independent experiments were performed. WEE1 expression in BON-1, NCI-H720 and QGP-1 cell lines. (C) Agarose gel electrophoresis (1.5% agarose) of WEE1 products of BON-1, NCI-H720 and QGP-1 cells in duplicates of one experiment. (D) qRT-PCR baseline expression analysis of WEE1 of BON-1, NCI-H720 and QGP-1 (n=1-3).
    • SUPPLEMENTARY FIGURE 2 DAPI vs. percentage of 𝛾H2AX+ cell fraction was measured with MACSQuant16 and analyzed via FlowJo. Representative flow cytometry plots are shown (0.01µM is not shown). The 𝛾H2AX/pHH3+ (orange) and 𝛾H2AX/<4N pHH3+ (red) subsets display an identical shift in DNA content distribution in overlay with overall 𝛾H2AX (green) for BON-1 (A), NCI-H720 (B) and QGP-1 (C).

 

Society for Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 838 838 73
Full Text Views 40 40 1
PDF Downloads 63 63 1
  • Basturk O, Yang Z, Tang LH, Hruban RH, Adsay V, McCall CM, Krasinskas AM, Jang KT, Frankel WL & Balci S et al.2015 The high-grade (WHO G3) pancreatic neuroendocrine tumor category is morphologically and biologically heterogenous and includes both well differentiated and poorly differentiated neoplasms. American Journal of Surgical Pathology 39 683690. (https://doi.org/10.1097/PAS.0000000000000408)

    • Search Google Scholar
    • Export Citation
  • Bauman JE & Chung CH 2014 CHK it out! Blocking WEE kinase routs TP53 mutant cancer. Clinical Cancer Research 20 41734175. (https://doi.org/10.1158/1078-0432.CCR-14-0720)

    • Search Google Scholar
    • Export Citation
  • Beck H, Nähse-Kumpf V, Larsen MS, O’Hanlon KA, Patzke S, Holmberg C, Mejlvang J, Groth A, Nielsen O & Syljuåsen RG et al.2012 Cyclin-dependent kinase suppression by Wee1 kinase protects the genome through control of replication initiation and nucleotide consumption. Molecular and Cellular Biology 32 42264236. (https://doi.org/10.1128/MCB.00412-12)

    • Search Google Scholar
    • Export Citation
  • Benten D, Behrang Y, Unrau L, Weissmann V, Wolters-Eisfeld G, Burdak-Rothkamm S, Stahl FR, Anlauf M, Grabowski P & Möbs M et al.2018 Establishment of the first well-differentiated human pancreatic neuroendocrine tumor model. Molecular Cancer Research 16 496507. (https://doi.org/10.1158/1541-7786.MCR-17-0163)

    • Search Google Scholar
    • Export Citation
  • Bi S, Wei Q, Zhao Z, Chen L, Wang C & Xie S 2019 Wee1 inhibitor AZD1775 effectively inhibits the malignant phenotypes of esophageal squamous cell carcinoma in vitro and in vivo. Frontiers in Pharmacology 10 864. (https://doi.org/10.3389/fphar.2019.00864)

    • Search Google Scholar
    • Export Citation
  • Bresciani G, Ditsiou A, Cilibrasi C, Vella V, Rea F, Schiavon M, Cavallesco NG, Giamas G, Zatelli MC & Gagliano T 2019 EGF and IGF1 affect sunitinib activity in BP-NEN: new putative targets beyond VEGFR? Endocrine Connections 8 680690. (https://doi.org/10.1530/EC-19-0192)

    • Search Google Scholar
    • Export Citation
  • Bridges KA, Hirai H, Buser CA, Brooks C, Liu H, Buchholz TA, Molkentine JM, Mason KA & Meyn RE 2011 MK-1775, a novel Wee1 kinase inhibitor, radiosensitizes p53-defective human tumor cells. Clinical Cancer Research 17 56385648. (https://doi.org/10.1158/1078-0432.CCR-11-0650)

    • Search Google Scholar
    • Export Citation
  • Chen W, Wong C, Vosburgh E, Levine AJ, Foran DJ & Xu EY 2014 High-throughput image analysis of tumor spheroids: a user-friendly software application to measure the size of spheroids automatically and accurately. Journal of Visualized Experiments 89 51639. (https://doi.org/10.3791/51639)

    • Search Google Scholar
    • Export Citation
  • Chen D, Lin X, Gao J, Shen L, Li Z, Dong B, Zhang C & Zhang X 2018 Wee1 inhibitor AZD1775 combined with cisplatin potentiates anticancer activity against gastric cancer by increasing DNA damage and cell apoptosis. BioMed Research International 2018 5813292. (https://doi.org/10.1155/2018/5813292)

    • Search Google Scholar
    • Export Citation
  • Costa EC, Moreira AF, de Melo-Diogo D, Gaspar VM, Carvalho MP & Correia IJ 2016 3D tumor spheroids: an overview on the tools and techniques used for their analysis. Biotechnology Advances 34 14271441. (https://doi.org/10.1016/j.biotechadv.2016.11.002)

    • Search Google Scholar
    • Export Citation
  • Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, Shih T & Yao JC 2017 Trends in the incidence, prevalence, and survival outcomes in patients with neuroendocrine tumors in the United States. JAMA Oncology 3 13351342. (https://doi.org/10.1001/jamaoncol.2017.0589)

    • Search Google Scholar
    • Export Citation
  • Di Ghelli Luserna Rorà A, Cerchione C, Martinelli G & Simonetti G 2020 A Wee1 family business: regulation of mitosis, cancer progression, and therapeutic target. Journal of Hematology and Oncology 1 126. (https://doi.org/10.1186/s13045-020-00959-2)

    • Search Google Scholar
    • Export Citation
  • Dietrich P, Gaza A, Wormser L, Fritz V, Hellerbrand C & Bosserhoff AK 2019 Neuroblastoma RAS viral oncogene homolog (NRAS) is a novel prognostic marker and contributes to sorafenib resistance in hepatocellular carcinoma. Neoplasia 21 257268. (https://doi.org/10.1016/j.neo.2018.11.011)

    • Search Google Scholar
    • Export Citation
  • Do K, Doroshow JH & Kummar S 2013 Wee1 kinase as a target for cancer therapy. Cell Cycle 1 2 31593164. (https://doi.org/10.4161/cc.26062)

  • Do K, Wilsker D, Ji J, Zlott J, Freshwater T, Kinders RJ, Collins J, Chen AP, Doroshow JH & Kummar S 2015 Phase I study of single-agent AZD1775 (MK-1775), a Wee1 kinase inhibitor, in patients with refractory solid tumors. Journal of Clinical Oncology 3 3 34093415. (https://doi.org/10.1200/JCO.2014.60.4009)

    • Search Google Scholar
    • Export Citation
  • Domínguez-Kelly R, Martín Y, Koundrioukoff S, Tanenbaum ME, Smits VA, Medema RH, Debatisse M & Freire R 2011 Wee1 controls genomic stability during replication by regulating the Mus81-Eme1 endonuclease. Journal of Cell Biology 19 4 567579. (https://doi.org/10.1083/jcb.201101047)

    • Search Google Scholar
    • Export Citation
  • Edmondson R, Broglie JJ, Adcock AF & Yang L 2014 Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay and Drug Development Technologies 12 207218. (https://doi.org/10.1089/adt.2014.573)

    • Search Google Scholar
    • Export Citation
  • Furlan D, Bernasconi B, Uccella S, Cerutti R, Carnevali I & Capella C 2005 Allelotypes and fluorescence in situ hybridization profiles of poorly differentiated endocrine carcinomas of different sites. Clinical Cancer Research 11 17651775. (https://doi.org/10.1158/1078-0432.CCR-04-1732)

    • Search Google Scholar
    • Export Citation
  • Garcia-Carbonero R, Capdevila J, Crespo-Herrero G, Díaz-Pérez JA, Martínez Del Prado MP, Alonso Orduña V, Sevilla-García I, Villabona-Artero C, Beguiristain-Gómez A & Llanos-Muñoz M et al.2010 Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE). Annals of Oncology 21 17941803. (https://doi.org/10.1093/annonc/mdq022)

    • Search Google Scholar
    • Export Citation
  • Garcia-Carbonero R, Sorbye H, Baudin E, Raymond E, Wiedenmann B, Niederle B, Sedlackova E, Toumpanakis C, Anlauf M & Cwikla JB et al.2016 ENETS consensus guidelines for high-grade gastroenteropancreatic neuroendocrine tumors and neuroendocrine carcinomas. Neuroendocrinology 103 186194. (https://doi.org/10.1159/000443172)

    • Search Google Scholar
    • Export Citation
  • George J, Walter V, Peifer M, Alexandrov LB, Seidel D, Leenders F, Maas L, Müller C, Dahmen I & Delhomme TM et al.2018 Integrative genomic profiling of large-cell neuroendocrine carcinomas reveals distinct subtypes of high-grade neuroendocrine lung tumors. Nature Communications 9 1048. (https://doi.org/10.1038/s41467-018-03099-x)

    • Search Google Scholar
    • Export Citation
  • Guertin AD, Li J, Liu Y, Hurd MS, Schuller AG, Long B, Hirsch HA, Feldman I, Benita Y & Toniatti C et al.2013 Preclinical evaluation of the WEE1 inhibitor MK-1775 as single-agent anticancer therapy. Molecular Cancer Therapeutics 12 14421452. (https://doi.org/10.1158/1535-7163.MCT-13-0025)

    • Search Google Scholar
    • Export Citation
  • Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G, Barriuso J, Pavel M, O’Toole D & Walter T et al.2015 Characteristics and treatment of patients with G3 gastroenteropancreatic neuroendocrine neoplasms. Endocrine-Related Cancer 22 657664. (https://doi.org/10.1530/ERC-15-0119)

    • Search Google Scholar
    • Export Citation
  • Herrera-Martínez AD, van den Dungen R, Dogan-Oruc F, van Koetsveld PM, Culler MD, Herder WW de, Luque RM, Feelders RA & Hofland LJ 2019 Effects of novel somatostatin-dopamine chimeric drugs in 2D and 3D cell culture models of neuroendocrine tumors. Endocrine-Related Cancer 2 6 585599. (https://doi.org/10.1530/ERC-19-0086)

    • Search Google Scholar
    • Export Citation
  • Hirai H, Iwasawa Y, Okada M, Arai T, Nishibata T, Kobayashi M, Kimura T, Kaneko N, Ohtani J & Yamanaka K et al.2009 Small-molecule inhibition of Wee1 kinase by MK-1775 selectively sensitizes p53-deficient tumor cells to DNA-damaging agents. Molecular Cancer Therapeutics 8 29923000. (https://doi.org/10.1158/1535-7163.MCT-09-0463)

    • Search Google Scholar
    • Export Citation
  • Hirai H, Arai T, Okada M, Nishibata T, Kobayashi M, Sakai N, Imagaki K, Ohtani J, Sakai T & Yoshizumi T et al.2010 MK-1775, a small molecule Wee1 inhibitor, enhances anti-tumor efficacy of various DNA-damaging agents, including 5-fluorouracil. Cancer Biology and Therapy 9 514522. (https://doi.org/10.4161/cbt.9.7.11115)

    • Search Google Scholar
    • Export Citation
  • Hofving T, Arvidsson Y, Almobarak B, Inge L, Pfragner R, Persson M, Stenman G, Kristiansson E, Johanson V & Nilsson O 2018 The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines. Endocrine-Related Cancer 3 367380. (https://doi.org/10.1530/ERC-17-0445)

    • Search Google Scholar
    • Export Citation
  • Jin J, Fang H, Yang F, Ji W, Guan N, Sun Z, Shi Y, Zhou G & Guan X 2018 Combined inhibition of ATR and WEE1 as a novel therapeutic strategy in triple-negative breast cancer. Neoplasia 20 478488. (https://doi.org/10.1016/j.neo.2018.03.003)

    • Search Google Scholar
    • Export Citation
  • Jin MH, Nam AR, Park JE, Bang JH, Bang YJ & Oh DY 2020 Therapeutic co-targeting of WEE1 and ATM downregulates PD-L1 expression in pancreatic cancer. Cancer Research and Treatment 52 149166. (https://doi.org/10.4143/crt.2019.183)

    • Search Google Scholar
    • Export Citation
  • Jong MRW de, Langendonk M, Reitsma B, Herbers P, Nijland M, Huls G, van den Berg A, Ammatuna E, Visser L & van Meerten T 2019 WEE1 inhibition enhances anti-apoptotic dependency as a result of premature mitotic entry and DNA damage. Cancers 11 1743. (https://doi.org/10.3390/cancers11111743)

    • Search Google Scholar
    • Export Citation
  • Jong MRW de, Langendonk M, Reitsma B, Herbers P, Lodewijk M, Nijland M, van den Berg A, Ammatuna E, Visser L & van Meerten T 2020 WEE1 inhibition synergizes with CHOP chemotherapy and radiation therapy through induction of premature mitotic entry and DNA damage in diffuse large B-cell lymphoma. Therapeutic Advances in Hematology 11 2040620719898373. (https://doi.org/10.1177/2040620719898373)

    • Search Google Scholar
    • Export Citation
  • Kao M, Green C, Sidorova J & Méndez E 2017 Strategies for targeted therapy in head and neck squamous cell carcinoma using WEE1 inhibitor AZD1775. JAMA Otolaryngology: Head and Neck Surgery 143 631633. (https://doi.org/10.1001/jamaoto.2016.4563)

    • Search Google Scholar
    • Export Citation
  • Kim HY, Cho Y, Kang H, Yim YS, Kim SJ, Song J & Chun KH 2016 Targeting the WEE1 kinase as a molecular targeted therapy for gastric cancer. Oncotarget 7 4990249916. (https://doi.org/10.18632/oncotarget.10231)

    • Search Google Scholar
    • Export Citation
  • Kreahling JM, Gemmer JY, Reed D, Letson D, Bui M & Altiok S 2012 MK1775, a selective Wee1 inhibitor, shows single-agent antitumor activity against sarcoma cells. Molecular Cancer Therapeutics 1 1 174182. (https://doi.org/10.1158/1535-7163.MCT-11-0529)

    • Search Google Scholar
    • Export Citation
  • Leijen S, van Geel RM, Pavlick AC, Tibes R, Rosen L, Razak AR, Lam R, Demuth T, Rose S & Lee MA et al.2016a Phase I study evaluating WEE1 inhibitor AZD1775 as monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors. Journal of Clinical Oncology 3 4 43714380. (https://doi.org/10.1200/JCO.2016.67.5991)

    • Search Google Scholar
    • Export Citation
  • Leijen S, van Geel RM, Sonke GS, Jong de D, Rosenberg EH, Marchetti S, Pluim D, van Werkhoven E, Rose S & Lee MA et al.2016b Phase II study of WEE1 inhibitor AZD1775 plus carboplatin in patients with TP53-mutated ovarian cancer refractory or resistant to first-line therapy within 3 months. Journal of Clinical Oncology 3 4 43544361. (https://doi.org/10.1200/JCO.2016.67.5942)

    • Search Google Scholar
    • Export Citation
  • Li AF, Tsay SH, Liang WY, Li WY & Chen JY 2006 Clinical significance of p16INK4a and p53 overexpression in endocrine tumors of the gastrointestinal tract. American Journal of Clinical Pathology 12 6 856865. (https://doi.org/10.1309/5X6WBYJ3U94EEKNN)

    • Search Google Scholar
    • Export Citation
  • Luley KB, Biedermann SB, Künstner A, Busch H, Franzenburg S, Schrader J, Grabowski P, Wellner UF, Keck T & Brabant G et al.2020 A comprehensive molecular characterization of the pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1. Cancers 12 691. (https://doi.org/10.3390/cancers12030691)

    • Search Google Scholar
    • Export Citation
  • Macheret M & Halazonetis TD 2015 DNA replication stress as a hallmark of cancer. Annual Review of Pathology 10 425448. (https://doi.org/10.1146/annurev-pathol-012414-040424)

    • Search Google Scholar
    • Export Citation
  • Matheson CJ, Backos DS & Reigan P 2016 Targeting WEE1 kinase in cancer. Trends in Pharmacological Sciences 37 872881. (https://doi.org/10.1016/j.tips.2016.06.006)

    • Search Google Scholar
    • Export Citation
  • McNamara MG, Scoazec JY & Walter T 2020 Extrapulmonary poorly differentiated NECs, including molecular and immune aspects. Endocrine-Related Cancer 2 7 R219R238. (https://doi.org/10.1530/ERC-19-0483)

    • Search Google Scholar
    • Export Citation
  • Méndez E, Rodriguez CP, Kao MC, Raju S, Diab A, Harbison RA, Konnick EQ, Mugundu GM, Santana-Davila R & Martins R et al.2018 A Phase I clinical trial of AZD1775 in combination with neoadjuvant weekly docetaxel and cisplatin before definitive therapy in head and neck squamous cell carcinoma. Clinical Cancer Research 24 27402748. (https://doi.org/10.1158/1078-0432.CCR-17-3796)

    • Search Google Scholar
    • Export Citation
  • Nuñez-Valdovinos B, Carmona-Bayonas A, Jimenez-Fonseca P, Capdevila J, Castaño-Pascual Á, Benavent M, Pi Barrio JJ, Teule A, Alonso V & Custodio A et al.2018 Neuroendocrine tumor heterogeneity adds uncertainty to the World Health Organization 2010 classification: real-world data from the Spanish Tumor Registry (R-GETNE). Oncologist 23 422432. (https://doi.org/10.1634/theoncologist.2017-0364)

    • Search Google Scholar
    • Export Citation
  • Osman AA, Monroe MM, Ortega Alves MV, Patel AA, Katsonis P, Fitzgerald AL, Neskey DM, Frederick MJ, Woo SH & Caulin C et al.2015 Wee-1 kinase inhibition overcomes cisplatin resistance associated with high-risk TP53 mutations in head and neck cancer through mitotic arrest followed by senescence. Molecular Cancer Therapeutics 14 608619. (https://doi.org/10.1158/1535-7163.MCT-14-0735-T)

    • Search Google Scholar
    • Export Citation
  • Oza AM, Weberpals JI, Provencher DM, Grischke E-M, Hall M, Uyar D, Estevez-Diz MDP, Marmé F, Kuzmin A & Rosenberg P et al.2015 An international, biomarker-directed, randomized, phase II trial of AZD1775 plus paclitaxel and carboplatin (P/C) for the treatment of women with platinum-sensitive, TP53 -mutant ovarian cancer. Journal of Clinical Oncology 33 55065506. (https://doi.org/10.1200/jco.2015.33.15_suppl.5506)

    • Search Google Scholar
    • Export Citation
  • Pavel ME & Sers C 2016 Women in cancer thematic review: systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine. Endocrine-Related Cancer 23 T135T154. (https://doi.org/10.1530/ERC-16-0370)

    • Search Google Scholar
    • Export Citation
  • Rajeshkumar NV, Oliveira de E, Ottenhof N, Watters J, Brooks D, Demuth T, Shumway SD, Mizuarai S, Hirai H & Maitra A et al.2011 MK-1775, a potent Wee1 inhibitor, synergizes with gemcitabine to achieve tumor regressions, selectively in p53-deficient pancreatic cancer xenografts. Clinical Cancer Research 17 27992806. (https://doi.org/10.1158/1078-0432.CCR-10-2580)

    • Search Google Scholar
    • Export Citation
  • Rouillard AD, Gundersen GW, Fernandez NF, Wang Z, Monteiro CD, McDermott MG & Ma’ayan A 2016 The harmonizome: a collection of processed datasets gathered to serve and mine knowledge about genes and proteins. Database 2016 baw100. (https://doi.org/10.1093/database/baw100)

    • Search Google Scholar
    • Export Citation
  • Sarcar B, Kahali S, Prabhu AH, Shumway SD, Xu Y, Demuth T & Chinnaiyan P 2011 Targeting radiation-induced G(2) checkpoint activation with the Wee-1 inhibitor MK-1775 in glioblastoma cell lines. Molecular Cancer Therapeutics 1 0 24052414. (https://doi.org/10.1158/1535-7163.MCT-11-0469)

    • Search Google Scholar
    • Export Citation
  • Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, Preibisch S, Rueden C, Saalfeld S, Schmid B, et al. 2012 Fiji: an open-source platform for biological-image analysis. Nature Methods 7 676682. (https://doi.org/10.1038/nmeth.2019)

    • Search Google Scholar
    • Export Citation
  • Schulz-Kuhnt A, Greif V, Hildner K, Knipfer L, Döbrönti M, Zirlik S, Fuchs F, Atreya R, Zundler S & López-Posadas R et al.2020 ILC2 lung-homing in cystic fibrosis patients: functional involvement of CCR6 and impact on respiratory failure. Frontiers in Immunology 11 691. (https://doi.org/10.3389/fimmu.2020.00691)

    • Search Google Scholar
    • Export Citation
  • Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, Dueland S, Hofsli E, Guren MG & Ohrling K et al.2013 Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study. Annals of Oncology 24 152160. (https://doi.org/10.1093/annonc/mds276)

    • Search Google Scholar
    • Export Citation
  • Sorbye H, Strosberg J, Baudin E, Klimstra DS & Yao JC 2014 Gastroenteropancreatic high-grade neuroendocrine carcinoma. Cancer 1 20 28142823. (https://doi.org/10.1002/cncr.28721)

    • Search Google Scholar
    • Export Citation
  • Sorbye H, Baudin E & Perren A 2018 The problem of high-grade gastroenteropancreatic neuroendocrine neoplasms: well-differentiated neuroendocrine tumors, neuroendocrine carcinomas, and beyond. Endocrinology and Metabolism Clinics of North America 47 683698. (https://doi.org/10.1016/j.ecl.2018.05.001)

    • Search Google Scholar
    • Export Citation
  • Tang LH, Untch BR, Reidy DL, O’Reilly E, Dhall D, Jih L, Basturk O, Allen PJ & Klimstra DS 2016 Well-differentiated neuroendocrine tumors with a morphologically apparent high-grade component: a pathway distinct from poorly differentiated neuroendocrine carcinomas. Clinical Cancer Research 22 10111017. (https://doi.org/10.1158/1078-0432.CCR-15-0548)

    • Search Google Scholar
    • Export Citation
  • Vandamme T, Peeters M, Dogan F, Pauwels P, van Assche E, Beyens M, Mortier G, Vandeweyer G, de Herder W & van Camp G et al.2015 Whole-exome characterization of pancreatic neuroendocrine tumor cell lines BON-1 and QGP-1. Journal of Molecular Endocrinology 54 137147. (https://doi.org/10.1530/JME-14-0304)

    • Search Google Scholar
    • Export Citation
  • Webster PJ, Littlejohns AT, Gaunt HJ, Prasad KR, Beech DJ & Burke DA 2017 AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in P53-mutated colorectal cancer cells. Cell Cycle 16 21762182. (https://doi.org/10.1080/15384101.2017.1301329)

    • Search Google Scholar
    • Export Citation
  • World Health Organization (WHO) 2019 WHO classification of tumours editorial board. In WHO Classification of Tumours: Digestive System Tumours. Lyon, France: IARC Press.

    • Search Google Scholar
    • Export Citation
  • Wong C, Vosburgh E, Levine AJ, Cong L & Xu EY 2012 Human neuroendocrine tumor cell lines as a three-dimensional model for the study of human neuroendocrine tumor therapy. Journal of Visualized Experiments 66 e4218. (https://doi.org/10.3791/4218)

    • Search Google Scholar
    • Export Citation
  • Yachida S, Vakiani E, White CM, Zhong Y, Saunders T, Morgan R, de Wilde RF, Maitra A, Hicks J & Demarzo AM et al.2012 Small cell and large cell neuroendocrine carcinomas of the pancreas are genetically similar and distinct from well-differentiated pancreatic neuroendocrine tumors. American Journal of Surgical Pathology 36 173184. (https://doi.org/10.1097/PAS.0b013e3182417d36)

    • Search Google Scholar
    • Export Citation
  • Young LA, O’Connor LO, de Renty C, Veldman-Jones MH, Dorval T, Wilson Z, Jones DR, Lawson D, Odedra R & Maya-Mendoza A et al.2019 Differential activity of ATR and WEE1 inhibitors in a highly sensitive subpopulation of DLBCL linked to replication stress. Cancer Research 79 37623775. (https://doi.org/10.1158/0008-5472.CAN-18-2480)

    • Search Google Scholar
    • Export Citation