Kinome rewiring during acquired drug resistance in neuroendocrine neoplasms

in Endocrine-Related Cancer
Authors:
Corinne Gérard Aix Marseille Univ, INSERM, MMG (U1251), Marseille Medical Genetics, Marseille, France

Search for other papers by Corinne Gérard in
Current site
Google Scholar
PubMed Close
,
Marie Lagarde Aix Marseille Univ, INSERM, MMG (U1251), Marseille Medical Genetics, Marseille, France

Search for other papers by Marie Lagarde in
Current site
Google Scholar
PubMed Close
,
Flora Poizat Medical Oncology Department, Paoli-Calmettes Institute CoE-ENETS, Marseille, France

Search for other papers by Flora Poizat in
Current site
Google Scholar
PubMed Close
,
Sandrine Oziel-Taieb Medical Oncology Department, Paoli-Calmettes Institute CoE-ENETS, Marseille, France

Search for other papers by Sandrine Oziel-Taieb in
Current site
Google Scholar
PubMed Close
,
Vincent Garcia Molecular Biology Laboratory, Hospital La Conception, AP-HM, Marseille, France

Search for other papers by Vincent Garcia in
Current site
Google Scholar
PubMed Close
,
Catherine Roche Molecular Biology Laboratory, Hospital La Conception, AP-HM, Marseille, France

Search for other papers by Catherine Roche in
Current site
Google Scholar
PubMed Close
,
Patricia Niccoli Medical Oncology Department, Paoli-Calmettes Institute CoE-ENETS, Marseille, France

Search for other papers by Patricia Niccoli in
Current site
Google Scholar
PubMed Close
,
Anne Barlier Aix Marseille Univ, INSERM, MMG (U1251), Marseille Medical Genetics, Marseille, France
Molecular Biology Laboratory, Hospital La Conception, AP-HM, Marseille, France

Search for other papers by Anne Barlier in
Current site
Google Scholar
PubMed Close
, and
David Romano Aix Marseille Univ, INSERM, MMG (U1251), Marseille Medical Genetics, Marseille, France

Search for other papers by David Romano in
Current site
Google Scholar
PubMed Close

Correspondence should be addressed to D Romano: romanodav@yahoo.fr
DOI:
https://doi.org/10.1530/ERC-19-0142
Volume/Issue:
Volume 28: Issue 1
Article Type:
Research Article
Page Range:
39–51
Online Publication Date:
Jan 2021
Copyright:
© 2021 Society for Endocrinology 2021
Restricted access
Rent on DeepDyve

Sign up for journal news

Although there is evidence of a significant rise of neuroendocrine neoplasms (NENs) incidence, current treatments are largely insufficient due to somewhat poor knowledge of these tumours. Despite showing differentiated features, NENs exhibit therapeutic resistance to most common treatments, similar to other cancers in many instances. Molecular mechanisms responsible for this resistance phenomenon are badly understood. We aimed at identifying signalling partners responsible of acquired resistance to treatments in order to develop novel therapeutic strategies. We engineered QGP-1 cells resistant to current leading treatments, the chemotherapeutic agent oxaliplatin and the mTor inhibitor everolimus. Cells were chronically exposed to the drugs and assessed for acquired resistance by viability assay. We used microarray-based kinomics to obtain highthroughput kinase activity profiles from drug sensitive vs resistant cells and identified ‘hit’ kinases hyperactivated in drug-resistant cells, including kinases from FGFR family, cyclin-dependant kinases and PKCs in oxaliplatin-resistant (R-Ox) QGP-1 cells. We then validated these ‘hit’ kinases and observed that ERK signalling is specifically enhanced in QGP-1 R-Ox cells. Finally, we assessed drug-resistant cells sensitivity to pharmacological inhibition of ‘hit’ kinases or their signalling partners. We found that FGFR inhibition markedly decreased ERK signalling and cell viability in QGP-1 R-Ox cells. These results suggest that the FGFR/ERK axis is hyperactivated in response to oxaliplatin-based chemotherapeutic strategy. Thus, this sensitive approach, based on the study of kinome activity, allows identifying potential candidates involved in drug resistance in NENs and may be used to broadly investigate markers of NENs therapeutic response.

Supplementary Materials

    • Supp. Fig.S1
    • Supp. Fig.S2
    • Supp. Fig.S3
    • Supp. Fig.S4
    • Supp. Fig.S5
    • Supp. Table S1
    • Supp. Table S2

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 610 18 0
PDF Downloads 398 10 0

 

  • Collapse
  • Expand
Print ISSN:
1351-0088
Online ISSN:
1479-6821
Copyright:
© 2021 Society for Endocrinology 2021
Page(s):
13
Received Date:
29 Sep 2020
Accepted Date:
22 Oct 2020
Print Publication Date:
01 Jan 2021
Online Publication Date:
Jan 2021
Keywords:
neuroendocrine neoplasms; therapeutic resistance; kinomic; signalling pathways

  • Ardito F, Giuliani M, Perrone D, Troiano G & Lo Muzio L 2017 The crucial role of protein phosphorylation in cell signaling and its use as targeted therapy (Review). International Journal of Molecular Medicine 40 271–280. (https://doi.org/10.3892/ijmm.2017.3036)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Aristizabal Prada ET & Auernhammer CJ 2018 Targeted therapy of gastroenteropancreatic neuroendocrine tumours: preclinical strategies and future targets. Endocrine Connections 7 R1–R25. (https://doi.org/10.1530/EC-17-0286)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Aristizabal Prada ET, Nölting S, Spoettl G, Maurer J & Auernhammer CJ 2018a The novel cyclin-dependent kinase 4/6 inhibitor Ribociclib (LEE011) alone and in dual-targeting approaches demonstrates antitumoral efficacy in neuroendocrine tumors in vitro. Neuroendocrinology 106 58–73. (https://doi.org/10.1159/000463386)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Aristizabal Prada ET, Spöttl G, Maurer J, Lauseker M, Koziolek EJ, Schrader J, Grossman A, Pacak K, Beuschlein F & Auernhammer CJ et al. 2018b The role of GSK3 and its reversal with GSK3 antagonism in everolimus resistance. Endocrine-Related Cancer 25 893–908. (https://doi.org/10.1530/ERC-18-0159)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Bajetta E, Catena L, Procopio G, De Dosso S, Bichisao E, Ferrari L, Martinetti A, Platania M, Verzoni E & Formisano B et al. 2007 Are capecitabine and oxaliplatin (XELOX) suitable treatments for progressing low-grade and high-grade neuroendocrine tumours? Cancer Chemotherapy and Pharmacology 59 637–642. (https://doi.org/10.1007/s00280-006-0306-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Beauchamp RD, Coffey Jr RJ, Lyons RM, Perkett EA, Townsend Jr CM & Moses HL 1991 Human carcinoid cell production of paracrine growth factors that can stimulate fibroblast and endothelial cell growth. Cancer Research 51 5253–5260.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Budde K, Zonnenberg BA, Frost M, Cheung W, Urva S, Brechenmacher T, Stein K, Chen D, Kingswood JC & Bissler JJ 2016 Pharmacokinetics and pharmacodynamics of everolimus in patients with renal angiomyolipoma and tuberous sclerosis complex or lymphangioleiomyomatosis. British Journal of Clinical Pharmacology 81 958–970. (https://doi.org/10.1111/bcp.12834)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Casimiro MC, Velasco-Velázquez M, Aguirre-Alvarado C & Pestell RG 2014 Overview of cyclins D1 function in cancer and the CDK inhibitor landscape: past and present. Expert Opinion on Investigational Drugs 23 295–304. (https://doi.org/10.1517/13543784.2014.867017)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Corbo V, Beghelli S, Bersani S, Antonello D, Talamini G, Brunelli M, Capelli P, Falconi M & Scarpa A 2012 Pancreatic endocrine tumours: mutational and immunohistochemical survey of protein kinases reveals alterations in targetable kinases in cancer cell lines and rare primaries. Annals of Oncology 23 127–134. (https://doi.org/10.1093/annonc/mdr048)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Di Florio A, Adesso L, Pedrotti S, Capurso G, Pilozzi E, Corbo V, Scarpa A, Geremia R, Delle Fave G & Sette C 2011 Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells. Endocrine-Related Cancer 18 541–554. (https://doi.org/10.1530/ERC-10-0153)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Dussol AS, Joly MO, Vercherat C, Forestier J, Hervieu V, Scoazec JY, Lombard-Bohas C & Walter T 2015 Gemcitabine and oxaliplatin or alkylating agents for neuroendocrine tumors: comparison of efficacy and search for predictive factors guiding treatment choice. Cancer 121 3428–3434. (https://doi.org/10.1002/cncr.29517)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Faure M, Niccoli P, Autret A, Cavaglione G, Mineur L & Raoul JL 2017 Systemic chemotherapy with FOLFOX in metastatic grade 1/2 neuroendocrine cancer. Molecular and Clinical Oncology 6 44–48. (https://doi.org/10.3892/mco.2016.1097)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Fleuren ED, Zhang L, Wu J & Daly RJ 2016 The kinome ‘at large’ in cancer. Nature Reviews: Cancer 16 83–98. (https://doi.org/10.1038/nrc.2015.18)

  • Girardi DM, Silva ACB, Rêgo JFM, Coudry RA & Riechelmann RP 2017 Unraveling molecular pathways of poorly differentiated neuroendocrine carcinomas of the gastroenteropancreatic system: a systematic review. Cancer Treatment Reviews 56 28–35. (https://doi.org/10.1016/j.ctrv.2017.04.002)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Graham MA, Lockwood GF, Greenslade D, Brienza S, Bayssas M & Gamelin E 2000 Clinical pharmacokinetics of oxaliplatin: a critical review. Clinical Cancer Research 6 1205–1218.

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Hadoux J, Malka D, Planchard D, Scoazec JY, Caramella C, Guigay J, Boige V, Leboulleux S, Burtin P & Berdelou A et al. 2015 Post-first-line FOLFOX chemotherapy for grade 3 neuroendocrine carcinoma. Endocrine-Related Cancer 22 289–298. (https://doi.org/10.1530/ERC-15-0075)

    • PubMed
    • 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 25 367–380. (https://doi.org/10.1530/ERC-17-0445)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Inzani F, Petrone G & Rindi G 2018 The New World Health Organization classification for pancreatic neuroendocrine neoplasia. Endocrinology and Metabolism Clinics of North America 47 463–470. (https://doi.org/10.1016/j.ecl.2018.04.008)

    • 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

  • Kawasaki K, Fujii M & Sato T 2018 Gastroenteropancreatic neuroendocrine neoplasms: genes, therapies and models. Disease Models and Mechanisms 11 dmm029595. (https://doi.org/10.1242/dmm.029595)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kidd M, Schimmack S, Lawrence B, Alaimo D & Modlin IM 2013 EGFR/TGFα and TGFβ/CTGF signaling in neuroendocrine neoplasia: theoretical therapeutic targets. Neuroendocrinology 97 35–44. (https://doi.org/10.1159/000334891)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Klempner SJ, Gershenhorn B, Tran P, Lee TK, Erlander MG, Gowen K, Schrock AB, Morosini D, Ross JS & Miller VA et al. 2016 BRAFV600E mutations in high-grade colorectal neuroendocrine tumors may predict responsiveness to BRAF-MEK combination therapy. Cancer Discovery 6 594–600. (https://doi.org/10.1158/2159-8290.CD-15-1192)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Konukiewitz B, Jesinghaus M, Steiger K, Schlitter AM, Kasajima A, Sipos B, Zamboni G, Weichert W, Pfarr N & Klöppel G 2018 Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3. Human Pathology 77 70–79. (https://doi.org/10.1016/j.humpath.2018.03.018)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Kulke MH 2017 Novel treatment options for neuroendocrine tumors. Journal of the National Comprehensive Cancer Network 15 737–739. (https://doi.org/10.6004/jnccn.2017.0088)

    • PubMed
    • 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)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Missiaglia E, Dalai I, Barbi S, Beghelli S, Falconi M, della Peruta M, Piemonti L, Capurso G, Di Florio A & delle Fave G et al. 2010 Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. Journal of Clinical Oncology 28 245–255. (https://doi.org/10.1200/JCO.2008.21.5988)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Mohamed A, Romano D, Saveanu A, Roche C, Albertelli M, Barbieri F, Brue T, Niccoli P, Delpero JR & Garcia S et al. 2017 Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs? Oncotarget 8 41044–41063. (https://doi.org/10.18632/oncotarget.17008)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Nölting S, Rentsch J, Freitag H, Detjen K, Briest F, Möbs M, Weissmann V, Siegmund B, Auernhammer CJ & Aristizabal Prada ET et al. 2017 The selective PI3Kα inhibitor BYL719 as a novel therapeutic option for neuroendocrine tumors: results from multiple cell line models. PLoS ONE 12 e0182852. (https://doi.org/10.1371/journal.pone.0182852)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Ohmoto A, Rokutan H & Yachida S 2017 Pancreatic neuroendocrine neoplasms: basic biology, current treatment strategies and prospects for the future. International Journal of Molecular Sciences 18 143. (https://doi.org/10.3390/ijms18010143)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Passacantilli I, Capurso G, Archibugi L, Calabretta S, Caldarola S, Loreni F, Delle Fave G & Sette C 2014 Combined therapy with RAD001 e BEZ235 overcomes resistance of PET immortalized cell lines to mTOR inhibition. Oncotarget 5 5381–5391. (https://doi.org/10.18632/oncotarget.2111)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pavel ME, Hainsworth JD, Baudin E, Peeters M, Hörsch D, Winkler RE, Klimovsky J, Lebwohl D, Jehl V & Wolin EM et al. 2011 Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study. Lancet 378 2005–2012. (https://doi.org/10.1016/S0140-6736(1161742-X)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, Krenning E, Knigge U, Salazar R & Pape UF et al. 2016 Enets consensus guidelines update for the management of distant metastatic disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN) and NEN of unknown primary site. Neuroendocrinology 103 172–185. (https://doi.org/10.1159/000443167)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Qian ZR, Ter-Minassian M, Chan JA, Imamura Y, Hooshmand SM, Kuchiba A, Morikawa T, Brais LK, Daskalova A & Heafield R et al. 2013 Prognostic significance of MTOR pathway component expression in neuroendocrine tumors. Journal of Clinical Oncology 31 3418–3425. (https://doi.org/10.1200/JCO.2012.46.6946)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Riddell IA & Lippard SJ 2018 Cisplatin and oxaliplatin: our current understanding of their actions. Metal Ions in Life Sciences 18 1–42. (https://doi.org/10.1515/9783110470734-001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Scarpa A, Chang DK, Nones K, Corbo V, Patch AM, Bailey P, Lawlor RT, Johns AL, Miller DK & Mafficini A et al. 2017 Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543 65–71. (https://doi.org/10.1038/nature21063)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Shamir ER, Devine WP, Pekmezci M, Umetsu SE, Krings G, Federman S, Cho SJ, Saunders TA, Jen KY & Bergsland E et al. 2019 Identification of high-risk human papillomavirus and Rb/E2F pathway genomic alterations in mutually exclusive subsets of colorectal neuroendocrine carcinoma. Modern Pathology 32 290–305. (https://doi.org/10.1038/s41379-018-0131-6)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Simbolo M, Vicentini C, Mafficini A, Fassan M, Pedron S, Corbo V, Mastracci L, Rusev B, Pedrazzani C & Landoni L et al. 2018 Mutational and copy number asset of primary sporadic neuroendocrine tumors of the small intestine. Virchows Archiv 473 709–717. (https://doi.org/10.1007/s00428-018-2450-x)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Spada F, Antonuzzo L, Marconcini R, Radice D, Antonuzzo A, Ricci S, Di Costanzo F, Fontana A, Gelsomino F & Luppi G et al. 2016 Oxaliplatin-based chemotherapy in advanced neuroendocrine tumors: clinical outcomes and preliminary correlation with biological factors. Neuroendocrinology 103 806–814. (https://doi.org/10.1159/000444087)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Valentino JD, Li J, Zaytseva YY, Mustain WC, Elliott VA, Kim JT, Harris JW, Campbell K, Weiss H & Wang C et al. 2014 Cotargeting the PI3K and RAS pathways for the treatment of neuroendocrine tumors. Clinical Cancer Research 20 1212–1222. (https://doi.org/10.1158/1078-0432.CCR-13-1897)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vandamme T, Beyens M, de Beeck KO, Dogan F, van Koetsveld PM, Pauwels P, Mortier G, Vangestel C, de Herder W & Van Camp G et al. 2016 Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. British Journal of Cancer 114 650–658. (https://doi.org/10.1038/bjc.2016.25)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Vranic S, Palazzo J, Sanati S, Florento E, Contreras E, Xiu J, Swensen J & Gatalica Z 2019 Potential novel therapy targets in neuroendocrine carcinomas of the breast. Clinical Breast Cancer 19 131–136. (https://doi.org/10.1016/j.clbc.2018.09.001)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Wilson LJ, Linley A, Hammond DE, Hood FE, Coulson JM, MacEwan DJ, Ross SJ, Slupsky JR, Smith PD & Eyers PA et al. 2018 New perspectives, opportunities, and challenges in exploring the human protein kinome. Cancer Research 78 15–29. (https://doi.org/10.1158/0008-5472.CAN-17-2291)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Xu C, Nezami Ranjbar MR, Wu Z, DiCarlo J & Wang Y 2017 Detecting very low allele fraction variants using targeted DNA sequencing and a novel molecular barcode-aware variant caller. BMC Genomics 18 5. (https://doi.org/10.1186/s12864-016-3425-4)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, Tomasek J, Raderer M, Lahner H & Voi M et al. 2016 Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet 387 968–977. (https://doi.org/10.1016/S0140-6736(1500817-X)

    • PubMed
    • Search Google Scholar
    • Export Citation

  • Zitzmann K, Rüden Jv, Brand S, Göke B, Lichtl J, Spöttl G & Auernhammer CJ 2010 Compensatory activation of Akt in response to mTOR and Raf inhibitors – a rationale for dual-targeted therapy approaches in neuroendocrine tumor disease. Cancer Letters 295 100–109. (https://doi.org/10.1016/j.canlet.2010.02.018)

    • PubMed
    • Search Google Scholar
    • Export Citation