Loss of MEN1 function impairs DNA repair capability of pancreatic neuroendocrine tumors

in Endocrine-Related Cancer
Authors:
Olga Lakiza Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

Search for other papers by Olga Lakiza in
Current site
Google Scholar
PubMed Close
,
Julian Lutze Committee on Cancer Biology, University of Chicago, Chicago, Illinois, USA

Search for other papers by Julian Lutze in
Current site
Google Scholar
PubMed Close
,
Alyx Vogle Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

Search for other papers by Alyx Vogle in
Current site
Google Scholar
PubMed Close
,
Jelani Williams Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

Search for other papers by Jelani Williams in
Current site
Google Scholar
PubMed Close
,
Abde Abukdheir Division of Hematology, Oncology, and Cell Therapy, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, USA

Search for other papers by Abde Abukdheir in
Current site
Google Scholar
PubMed Close
,
Paul Miller Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

Search for other papers by Paul Miller in
Current site
Google Scholar
PubMed Close
,
Chih-Yi ‘Andy’ Liao Division of Hematology and Oncology, Department of Internal Medicine, University of Chicago, Chicago, Illinois, USA

Search for other papers by Chih-Yi ‘Andy’ Liao in
Current site
Google Scholar
PubMed Close
,
Sean P Pitroda Department of Radiation Oncology and Cellular Biology, University of Chicago, Chicago, Illinois, USA

Search for other papers by Sean P Pitroda in
Current site
Google Scholar
PubMed Close
,
Carlos Martinez Department of Radiation Oncology and Cellular Biology, University of Chicago, Chicago, Illinois, USA

Search for other papers by Carlos Martinez in
Current site
Google Scholar
PubMed Close
,
Andrea Olivas Department of Pathology, University of Chicago, Chicago, Illinois, USA

Search for other papers by Andrea Olivas in
Current site
Google Scholar
PubMed Close
,
Namrata Setia Department of Pathology, University of Chicago, Chicago, Illinois, USA

Search for other papers by Namrata Setia in
Current site
Google Scholar
PubMed Close
,
Stephen J Kron Committee on Cancer Biology, University of Chicago, Chicago, Illinois, USA
Department of Molecular Genetics and Cell Biology, University of Chicago, Chicago, Illinois, USA

Search for other papers by Stephen J Kron in
Current site
Google Scholar
PubMed Close
,
Ralph R Weichselbaum Department of Radiation Oncology and Cellular Biology, University of Chicago, Chicago, Illinois, USA
Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois, USA

Search for other papers by Ralph R Weichselbaum in
Current site
Google Scholar
PubMed Close
, and
Xavier M Keutgen Endocrine and Neuroendocrine Surgery Research Program, Division of General Surgery and Surgical Oncology, Department of Surgery, University of Chicago Medicine, Chicago, Illinois, USA

Search for other papers by Xavier M Keutgen in
Current site
Google Scholar
PubMed Close
https://orcid.org/0000-0002-4627-3560

Correspondence should be addressed to X M Keutgen: xkeutgen@surgery.bsd.uchicago.edu

†The work herein was completed while AMA was a faculty member at Rush University. AMA is currently an employee with the U.S. Food and Drug Administration. The views and data in this publication do not reflect the opinions of the U.S. Food and Drug Administration.

DOI:
https://doi.org/10.1530/ERC-21-0247
Volume/Issue:
Volume 29: Issue 4
Article Type:
Research Article
Page Range:
225–239
Online Publication Date:
21 Mar 2022
Copyright:
© Society for Endocrinology 2022
Restricted access
Rent on DeepDyve

Sign up for journal news

Somatic MEN1 mutations occur in up to 50% of pancreatic neuroendocrine tumors (PanNETs). Clinical studies have shown that radiation therapy (IR) is effective in a subset of PanNETs, but it remains unclear why some patients respond better to IR than others. Herein, we study whether MEN1 loss of function increases radiosensitivity of PanNETs and determine its effect on DNA double-strand break (DSB) repair. After creating a MEN1 knockout PanNET cell line, we confirmed reduced DSB repair capacity in MEN1-deficient cells and linked these findings to a defect in homologous recombination, as well as reduced BRCA2 expression levels. Consistent with this model, we found that MEN1 mutant cells displayed increased sensitivity to the highly trapping poly (ADP-ribose) polymerase (PARP) 1 inhibitor talazoparib in vitro. Our results suggest that combining IR with PARP inhibition may be beneficial in patients with PanNETs and MEN1 loss of function.

Endocrine-Related Cancer is committed to supporting researchers in demonstrating the impact of their articles published in the journal.

The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.

More information is on the Reasons to publish page.

Sept 2018 onwards Past Year Past 30 Days
Full Text Views 618 77 2
PDF Downloads 345 40 1

 

  • Collapse
  • Expand
Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© Society for Endocrinology 2022
Page(s):
15
Received Date:
14 Feb 2022
Accepted Date:
16 Feb 2022
Print Publication Date:
01 Apr 2022
Online Publication Date:
21 Mar 2022
Keywords:
DNA damage; MEN1; homologous recombination; BRCA2; pancreatic NETs

  • Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA, de Herder WW, van Eijck CHJ, Franssen GJH, Krenning EP & Kwekkeboom DJ 2017 Long-term efficacy, survival, and safety of [(177)Lu-DOTA(0),Tyr(3)]octreotate in patients with gastroenteropancreatic and bronchial neuroendocrine tumors. Clinical Cancer Research 23 4617–4624. (https://doi.org/10.1158/1078-0432.CCR-16-2743)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ & Helleday T 2005 Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434 913–917. (https://doi.org/10.1038/nature03443)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, Cadiot G, Wolin EM, Capdevila J & Wall L et al.2014 Lanreotide in metastatic enteropancreatic neuroendocrine tumors. New England Journal of Medicine 371 224–233. (https://doi.org/10.1056/NEJMoa1316158)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Caron MC, Sharma AK, O’Sullivan J, Myler LR, Ferreira MT, Rodrigue A, Coulombe Y, Ethier C, Gagne JP & Langelier MF et al.2019 Poly(ADP-ribose) polymerase-1 antagonizes DNA resection at double-strand breaks. Nature Communications 10 2954. (https://doi.org/10.1038/s41467-019-10741-9)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cejas P, Drier Y, Dreijerink KMA, Brosens LAA, Deshpande V, Epstein CB, Conemans EB, Morsink FHM, Graham MK & Valk GD et al.2019 Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors. Nature Medicine 25 1260–1265. (https://doi.org/10.1038/s41591-019-0493-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chan CS, Laddha SV, Lewis PW, Koletsky MS, Robzyk K, Da Silva E, Torres PJ, Untch BR, Li J & Bose P et al.2018a ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup. Nature Communications 9 4158. (https://doi.org/10.1038/s41467-018-06498-2)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Chan DL, Thompson R, Lam M, Pavlakis N, Hallet J, Law C, Singh S & Myrehaug S 2018b External beam radiotherapy in the treatment of gastroenteropancreatic neuroendocrine tumours: a systematic review. Clinical Oncology 30 400–408. (https://doi.org/10.1016/j.clon.2018.03.006)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Cullinane C, Waldeck K, Kirby L, Rogers BE, Eu P, Tothill RW & Hicks RJ 2020 Enhancing the anti-tumour activity of (177)Lu-DOTA-octreotate radionuclide therapy in somatostatin receptor-2 expressing tumour models by targeting PARP. Scientific Reports 10 10196. (https://doi.org/10.1038/s41598-020-67199-9)

    • PubMed
    • 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 1335–1342. (https://doi.org/10.1001/jamaoncol.2017.0589)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dreijerink KMA, Timmers HTM & Brown M 2017 Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Endocrine-Related Cancer 24 T135–T145. (https://doi.org/10.1530/ERC-17-0281)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Efimova EV, Liang H, Pitroda SP, Labay E, Darga TE, Levina V, Lokshin A, Roizman B, Weichselbaum RR & Khodarev NN 2009 Radioresistance of Stat1 over-expressing tumour cells is associated with suppressed apoptotic response to cytotoxic agents and increased IL6-IL8 signalling. International Journal of Radiation Biology 85 421–431. (https://doi.org/10.1080/09553000902838566)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Evers BM, Townsend CM Jr, Upp JR, Allen E, Hurlbut SC, Kim SW, Rajaraman S, Singh P, Reubi JC & Thompson JC 1991 Establishment and characterization of a human carcinoid in nude mice and effect of various agents on tumor growth. Gastroenterology 101 303–311. (https://doi.org/10.1016/0016-5085(9190004-5)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fang M, Xia F, Mahalingam M, Virbasius CM, Wajapeyee N & Green MR 2013 MEN1 is a melanoma tumor suppressor that preserves genomic integrity by stimulating transcription of genes that promote homologous recombination-directed DNA repair. Molecular and Cellular Biology 33 2635–2647. (https://doi.org/10.1128/MCB.00167-13)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Gallo A, Agnese S, Esposito I, Galgani M & Avvedimento VE 2010 Menin stimulates homology-directed DNA repair. FEBS Letters 584 4531–4536. (https://doi.org/10.1016/j.febslet.2010.10.032)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Heeke AL, Pishvaian MJ, Lynce F, Xiu J, Brody JR, Chen WJ, Baker TM, Marshall JL & Isaacs C 2018 Prevalence of homologous recombination-related gene mutations Across multiple cancer types. JCO Precision Oncology 2018 PO.17.00286. (https://doi.org/10.1200/PO.17.00286)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Jiao Y, Shi C, Edil BH, de Wilde RF, Klimstra DS, Maitra A, Schulick RD, Tang LH, Wolfgang CL & Choti MA et al.2011 DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331 1199–1203. (https://doi.org/10.1126/science.1200609)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Keutgen XM, Schadde E, Pommier RF, Halfdanarson TR, Howe JR & Kebebew E 2018 Metastatic neuroendocrine tumors of the gastrointestinal tract and pancreas: a surgeon’s plea to centering attention on the liver. Seminars in Oncology 45 232–235. (https://doi.org/10.1053/j.seminoncol.2018.07.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kotter A, Cornils K, Borgmann K, Dahm-Daphi J, Petersen C, Dikomey E & Mansour WY 2014 Inhibition of PARP1-dependent end-joining contributes to Olaparib-mediated radiosensitization in tumor cells. Molecular Oncology 8 1616–1625. (https://doi.org/10.1016/j.molonc.2014.06.008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Lord CJ & Ashworth A 2017 PARP inhibitors: synthetic lethality in the clinic. Science 355 1152–1158. (https://doi.org/10.1126/science.aam7344)

  • Mafficini A & Scarpa A 2018 Genomic landscape of pancreatic neuroendocrine tumours: the International Cancer Genome Consortium. Journal of Endocrinology 236 R161–R167. (https://doi.org/10.1530/JOE-17-0560)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Malcolm J, Falzone N, Lee BQ & Vallis KA 2019 Targeted radionuclide therapy: new advances for improvement of patient management and response. Cancers 11 268. (https://doi.org/10.3390/cancers11020268)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Monazzam A, Li SC, Wargelius H, Razmara M, Bajic D, Mi J, Bergquist J, Crona J & Skogseid B 2020 Generation and characterization of CRISPR/Cas9-mediated MEN1 knockout BON1 cells: a human pancreatic neuroendocrine cell line. Scientific Reports 10 14572. (https://doi.org/10.1038/s41598-020-71516-7)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Murai J, Huang SY, Das BB, Renaud A, Zhang Y, Doroshow JH, Ji J, Takeda S & Pommier Y 2012 Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Research 72 5588–5599. (https://doi.org/10.1158/0008-5472.CAN-12-2753)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pape UF, Berndt U, Muller-Nordhorn J, Bohmig M, Roll S, Koch M, Willich SN & Wiedenmann B 2008 Prognostic factors of long-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocrine-Related Cancer 15 1083–1097. (https://doi.org/10.1677/ERC-08-0017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Parsels LA, Karnak D, Parsels JD, Zhang Q, Velez-Padilla J, Reichert ZR, Wahl DR, Maybaum J, O’Connor MJ & Lawrence TS et al.2018 PARP1 trapping and DNA replication stress enhance radiosensitization with combined WEE1 and PARP inhibitors. Molecular Cancer Research 16 222–232. (https://doi.org/10.1158/1541-7786.MCR-17-0455)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Peixoto RD, Noonan KL, Pavlovich P, Kennecke HF & Lim HJ 2014 Outcomes of patients treated with capecitabine and temozolamide for advanced pancreatic neuroendocrine tumors (PNETs) and non-PNETs. Journal of Gastrointestinal Oncology 5 247–252. (https://doi.org/10.3978/j.issn.2078-6891.2014.019)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Prakash R, Zhang Y, Feng W & Jasin M 2015 Homologous recombination and human health: the roles of BRCA1, BRCA2, and associated proteins. Cold Spring Harbor Perspectives in Biology 7 a016600. (https://doi.org/10.1101/cshperspect.a016600)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Qiu H, Jin BM, Wang ZF, Xu B, Zheng QF, Zhang L, Zhu LY, Shi S, Yuan JB & Lin X et al.2020 MEN1 deficiency leads to neuroendocrine differentiation of lung cancer and disrupts the DNA damage response. Nature Communications 11 1009. (https://doi.org/10.1038/s41467-020-14614-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Raymond E, Dahan L, Raoul JL, Bang YJ, Borbath I, Lombard-Bohas C, Valle J, Metrakos P, Smith D & Vinik A et al.2011 Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. New England Journal of Medicine 364 501–513. (https://doi.org/10.1056/NEJMoa1003825)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Salloum RM, Jaskowiak NT, Mauceri HJ, Seetharam S, Beckett MA, Koons AM, Hari DM, Gupta VK, Reimer C & Kalluri R et al.2000 NM-3, an isocoumarin, increases the antitumor effects of radiotherapy without toxicity. Cancer Research 60 6958–6963.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Scully R, Panday A, Elango R & Willis NA 2019 DNA double-strand break repair-pathway choice in somatic mammalian cells. Nature Reviews: Molecular Cell Biology 20 698–714. (https://doi.org/10.1038/s41580-019-0152-0)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shibata A & Jeggo PA 2020 Roles for 53BP1 in the repair of radiation-induced DNA double strand breaks. DNA Repair 93 102915. (https://doi.org/10.1016/j.dnarep.2020.102915)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, Mittra E, Kunz PL, Kulke MH & Jacene H et al.2017 Phase 3 trial of (177)Lu-Dotatate for midgut neuroendocrine tumors. New England Journal of Medicine 376 125–135. (https://doi.org/10.1056/NEJMoa1607427)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR & Lander ES et al.2005 Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. PNAS 102 15545–15550. (https://doi.org/10.1073/pnas.0506580102)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Sullivan MR & Bernstein KA 2018 RAD-iCal new insights into RAD51 regulation. Genes 9 629. (https://doi.org/10.3390/genes9120629)

  • 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 54 137–147. (https://doi.org/10.1530/JME-14-0304)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Woltering EA, Voros BA, Beyer DT, Wang YZ, Thiagarajan R, Ryan P, Wright A, Ramirez RA, Ricks MJ & Boudreaux JP 2017 Aggressive surgical approach to the management of neuroendocrine tumors: a report of 1000 surgical cytoreductions by a single institution. Journal of the American College of Surgeons 224 434–447. (https://doi.org/10.1016/j.jamcollsurg.2016.12.032)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yamaguchi N, Uozumi G, Ikeuchi H, Morioka H, Machino M & Kawai K 1983 Establishment and characterization of a carcinoembryonic antigen producing cell line derived from human pancreatic exocrine cancer. Gastroenterologia Japonica 18 585–592. (https://doi.org/10.1007/BF02774699)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, Hobday TJ, Okusaka T, Capdevila J & de Vries EG et al.2011 Everolimus for advanced pancreatic neuroendocrine tumors. New England Journal of Medicine 364 514–523. (https://doi.org/10.1056/NEJMoa1009290)

    • PubMed
    • Search Google Scholar
    • Export Citation