Summary
Pancreatic cancer is one of the most common causes of cancer-related mortality in the Western world and pancreatic ductal adenocarcinoma (PDAC) is by far the most common pancreatic cancer entity. Locally advanced or metastatic PDAC remains a major clinical challenge, and the prognosis of affected patients is dismal despite substantial research efforts in this area. Recent large-scale genomic analyses of PDAC revealed that KRAS is the most frequently mutated driver gene in this entity. In addition, a relatively large proportion of PDAC patients displays germline variants in genes involved in DNA repair, particularly DNA double-strand repair. Similarly, a sizable fraction of sporadic PDAC cases harbor mutations in genome maintenance genes, such as BRCA1, BRCA2, and ATM. While direct targeting of oncogenic KRAS is currently not possible in the clinical setting, these defects in DNA repair may open new therapeutic avenues. Here, we discuss the potential use of compounds that interfere with DNA repair and genome maintenance mechanisms for the treatment of PDAC. We particularly focus on the genotype-tailored use of compounds, such as PARP inhibitors, as well as ATR- and DNA-protein kinase catalytic subunit (PKcs) inhibitors.
Journal Section:
Review Article
References
1.
Krebs in Deutschland 2005/2006 Haeufigkeiten und Trends. Berlin, 2010.
2.
Maitra A, Hruban RH: Pancreatic cancer. Annu Rev Pathol 2008;3:157-188.
[PubMed]
3.
Siegel RL, Miller KD, Jemal A: Cancer statistics, 2015. CA Cancer J Clin 2015;65:5-29.
[PubMed]
4.
Rahib L, Smith BD, Aizenberg R, et al.: Projecting cancer incidence and deaths to 2030: The unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-2921.
[PubMed]
5.
Jemal A, Siegel R, Xu J, Ward E: Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
[PubMed]
6.
Vaccaro V, Melisi D, Bria E, et al.: Emerging pathways and future targets for the molecular therapy of pancreatic cancer. Expert Opin Ther Targets 2011;15:1183-1196.
[PubMed]
7.
Saif MW: Pancreatic neoplasm in 2011: An update. JOP 2011;12:316-321.
[PubMed]
8.
Burris HA 3rd, Moore MJ, Andersen J, et al.: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 1997;15:2403-2413.
[PubMed]
9.
Moore MJ, Goldstein D, Hamm J, et al.: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2007;25:1960-1966.
[PubMed]
10.
Conroy T, Desseigne F, Ychou M, et al.: FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 2011;364:1817-1825.
[PubMed]
11.
Von Hoff DD, Ervin T, Arena FP, et al.: Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:1691-1703.
[PubMed]
12.
Wang-Gillam A, Li CP, Bodoky G, et al.: Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): A global, randomised, open-label, phase 3 trial. Lancet 2016;387:545-557.
[PubMed]
13.
Scarpa A, Chang DK, Nones K, et al.: Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 2017;543:65-71.
[PubMed]
14.
Bailey P, Chang DK, Nones K, et al.: Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 2016;531:47-52.
[PubMed]
15.
Waddell N, Pajic M, Patch AM, et al.: Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 2015;518:495-501.
[PubMed]
16.
Alexandrov LB, Nik-Zainal S, Wedge DC, et al.: Signatures of mutational processes in human cancer. Nature 2013;500:415-421.
[PubMed]
17.
Biankin AV, Waddell N, Kassahn KS, et al.: Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 2012;491:399-405.
[PubMed]
18.
Cancer Genome Atlas Research Network, Electronic address: andrew_aguirre@dfci.harvard.edu: Integrated genomic characterization of pancreatic ductal adenocarcinoma. Cancer Cell 2017;32:185-203.
[PubMed]
19.
Jones S, Hruban RH, Kamiyama M, et al.: Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science 2009;324:217.
[PubMed]
20.
Slater EP, Langer P, Niemczyk E, et al.: PALB2 mutations in European familial pancreatic cancer families. Clin Genet 2010;78:490-494.
[PubMed]
21.
Yurgelun MB, Chittenden AB, Morales-Oyarvide V, et al.: Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med 2018;doi:10.1038/s41436-018-0009-5 [Epub ahead of print].
[PubMed]
22.
Hu C, Hart SN, Polley EC, et al.: Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer. JAMA 2018;319:2401-2409.
[PubMed]
23.
Young EL, Thompson BA, Neklason DW, et al.: Pancreatic cancer as a sentinel for hereditary cancer predisposition. BMC Cancer 2018;18:697.
[PubMed]
24.
Prakash S, Johnson RE, Prakash L: Eukaryotic translesion synthesis DNA polymerases: Specificity of structure and function. Annu Rev Biochem 2005;74:317-353.
[PubMed]
25.
Dietlein F, Thelen L, Reinhardt HC: Cancer-specific defects in DNA repair pathways as targets for personalized therapeutic approaches. Trends Genet 2014;30:326-339.
[PubMed]
26.
Ciriello G, Miller ML, Aksoy BA, et al.: Emerging landscape of oncogenic signatures across human cancers. Nat Genet 2013;45:1127-1133.
[PubMed]
27.
Reinhardt HC, Jiang H, Hemann MT, Yaffe MB: Exploiting synthetic lethal interactions for targeted cancer therapy. Cell Cycle 2009;8:3112-3119.
[PubMed]
28.
Loeb LA, Bielas JH, Beckman RA: Cancers exhibit a mutator phenotype: Clinical implications. Cancer Res 2008;68:3551-3557; discussion 3557.
[PubMed]
29.
Chapman JR, Taylor MR, Boulton SJ: Playing the end game: DNA double-strand break repair pathway choice. Mol Cell 2012;47:497-510.
[PubMed]
30.
Lyndaker AM, Alani E: A tale of tails: insights into the coordination of 3' end processing during homologous recombination. BioEssays 2009;31:315-321.
[PubMed]
31.
Cimprich KA, Cortez D: ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 2008;9:616-627.
[PubMed]
32.
Krejci L, Altmannova V, Spirek M, Zhao X: Homologous recombination and its regulation. Nucleic Acids Res 2012;40:5795-5818.
[PubMed]
33.
San Filippo J, Sung P, Klein H: Mechanism of eukaryotic homologous recombination. Annu Rev Biochem 2008;77:229-257.
[PubMed]
34.
Sung P, Klein H: Mechanism of homologous recombination: mediators and helicases take on regulatory functions. Nat Rev Mol Cell Biol 2006;7:739-750.
[PubMed]
35.
Heyer WD, Ehmsen KT, Liu J: Regulation of homologous recombination in eukaryotes. Annu Rev Genet 2010;44:113-139.
[PubMed]
36.
Venkitaraman AR: Tracing the network connecting BRCA and Fanconi anaemia proteins. Nat Rev Cancer 2004;4:266-276.
[PubMed]
37.
Meindl A, Hellebrand H, Wiek C, et al.: Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 2010;42:410-414.
[PubMed]
38.
Al-Sukhni W, Rothenmund H, Borgida AE, et al.: Germline BRCA1 mutations predispose to pancreatic adenocarcinoma. Hum Genet 2008;124:271-278.
[PubMed]
39.
Bartsch DK, Gress TM, Langer P: Familial pancreatic cancer-current knowledge. Nature Rev Gastroenterol Hepatol 2012;9:445-453.
[PubMed]
40.
Greer JB, Whitcomb DC: Role of BRCA1 and BRCA2 mutations in pancreatic cancer. Gut 2007;56:601-605.
[PubMed]
41.
Ding L, Getz G, Wheeler DA, et al.: Somatic mutations affect key pathways in lung adenocarcinoma. Nature 2008;455:1069-1075.
[PubMed]
42.
Network TCGAR: Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-615.
[PubMed]
43.
Puente XS, Pinyol M, Quesada V, et al.: Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia. Nature 2011;475:101-105.
[PubMed]
44.
Quesada V, Conde L, Villamor N, et al.: Exome sequencing identifies recurrent mutations of the splicing factor SF3B1 gene in chronic lymphocytic leukemia. Nat Genet 2011;44:47-52.
[PubMed]
45.
Yang P, Zhang W, Wang J, et al.: Genomic landscape and prognostic analysis of mantle cell lymphoma. Cancer gene therapy 2018;doi:10.1038/s41417-018-0022-5 [Epub ahead of print].
[PubMed]
46.
Schrader A, Crispatzu G, Oberbeck S, et al.: Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL. Nat Commun 2018;9:697.
[PubMed]
47.
Hartlerode AJ, Scully R: Mechanisms of double-strand break repair in somatic mammalian cells. Biochem J 2009;423:157-168.
[PubMed]
48.
Dietlein F, Reinhardt HC: Molecular pathways: exploiting tumor-specific molecular defects in DNA repair pathways for precision cancer therapy. Clin Cancer Res 2014;20:5882-5887.
[PubMed]
49.
Lees-Miller SP, Meek K: Repair of DNA double strand breaks by non-homologous end joining. Biochimie 2003;85:1161-1173.
[PubMed]
50.
Chang HHY, Pannunzio NR, Adachi N, Lieber MR: Non-homologous DNA end joining and alternative pathways to double-strand break repair. Nat Rev Mol Cell Biol 2017;18:495-506.
[PubMed]
51.
Karnoub AE, Weinberg RA: Ras oncogenes: Split personalities. Nat Rev Mol Cell Biol 2008;9:517-531.
[PubMed]
52.
Clinical Lung Cancer Genome P, Network Genomic M: A genomics-based classification of human lung tumors. Sci Transl Med 2013;5:209ra153.
[PubMed]
53.
Fisher GH, Wellen SL, Klimstra D, et al.: Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 2001;15:3249-3262.
[PubMed]
54.
Zimmermann G, Papke B, Ismail S, et al.: Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling. Nature 2013;497:638-642.
[PubMed]
55.
Ostrem JM, Peters U, Sos ML, et al.: K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 2013;503:548-551.
[PubMed]
56.
Scholl C, Frohling S, Dunn IF, et al.: Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 2009;137:821-834.
[PubMed]
57.
Luo T, Masson K, Jaffe JD, et al.: STK33 kinase inhibitor BRD-8899 has no effect on KRAS-dependent cancer cell viability. Proc Natl Acad Sci USA 2012;109:2860-2865.
[PubMed]
58.
Babij C, Zhang Y, Kurzeja RJ, et al.: STK33 kinase activity is nonessential in KRAS-dependent cancer cells. Cancer Res 2011;71:5818-5826.
[PubMed]
59.
Frohling S, Scholl C: STK33 kinase is not essential in KRAS-dependent cells-letter. Cancer Res 2011;71:7716; author reply 7717.
[PubMed]
60.
Long GV, Stroyakovskiy D, Gogas H, et al.: Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877-1888.
[PubMed]
61.
Flaherty KT, Infante JR, Daud A, et al.: Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694-1703.
[PubMed]
62.
Engelman JA, Chen L, Tan X, et al.: Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-1356.
[PubMed]
63.
Britten CD: PI3K and MEK inhibitor combinations: Examining the evidence in selected tumor types. Cancer Chemother Pharmacol 2013;71:1395-1409.
[PubMed]
64.
Mainardi S, Mulero-Sanchez A, Prahallad A, et al.: SHP2 is required for growth of KRAS-mutant non-small-cell lung cancer in vivo. Nat Med 2018;24:961-967.
[PubMed]
65.
Ruess DA, Heynen GJ, Ciecielski KJ, et al.: Mutant KRAS-driven cancers depend on PTPN11/SHP2 phosphatase. Nat Med 2018;24:954-960.
[PubMed]
66.
Wong GS, Zhou J, Liu JB, et al.: Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition. Nat Med 2018;24:968-977.
[PubMed]
67.
Grabocka E, Commisso C, Bar-Sagi D: Molecular pathways: Targeting the dependence of mutant RAS cancers on the DNA damage response. Clin Cancer Res 2015;21:1243-1247.
[PubMed]
68.
Grabocka E, Pylayeva-Gupta Y, Jones MJ, et al.: Wild-type H- and N-Ras promote mutant K-Ras-driven tumorigenesis by modulating the DNA damage response. Cancer Cell 2014;25:243-256.
[PubMed]
69.
Morgan MA, Parsels LA, Zhao L, et al.: Mechanism of radiosensitization by the Chk1/2 inhibitor AZD7762 involves abrogation of the G2 checkpoint and inhibition of homologous recombinational DNA repair. Cancer Res 2010;70:4972-4981.
[PubMed]
70.
Kleiman LB, Krebs AM, Kim SY, et al.: Comparative analysis of radiosensitizers for K-RAS mutant rectal cancers. PLoS One 2013;8:e82982.
[PubMed]
71.
Dietlein F, Kalb B, Jokic M, et al.: A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer. Cell 2015;162:146-159.
[PubMed]
72.
Kaelin WG Jr: The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer 2005;5:689-698.
[PubMed]
73.
Bryant HE, Schultz N, Thomas HD, et al.: Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase. Nature 2005;434:913-917.
[PubMed]
74.
Farmer H, McCabe N, Lord CJ, et al.: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-921.
[PubMed]
75.
Robson M, Im SA, Senkus E, et al.: Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med 2017;377:523-533.
[PubMed]
76.
Kaufman B, Shapira-Frommer R, Schmutzler RK, et al.: Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol 2015;33:244-250.
[PubMed]
77.
McCabe N, Turner NC, Lord CJ, et al.: Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 2006;66:8109-8115.
[PubMed]
78.
Perkhofer L, Schmitt A, Romero Carrasco MC, et al.: ATM deficiency generating genomic instability sensitizes pancreatic ductal adenocarcinoma cells to therapy-induced DNA damage. Cancer Res 2017;77:5576-5590.
[PubMed]
79.
Knittel G, Liedgens P, Reinhardt HC: Targeting ATM-deficient CLL through interference with DNA repair pathways. Front Genet 2015;6:207.
[PubMed]
80.
Knittel G, Rehkamper T, Korovkina D, et al.: Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun 2017;8:153.
[PubMed]
81.
Schmitt A, Knittel G, Welcker D, et al.: ATM deficiency is associated with sensitivity to PARP1 and ATR inhibitors in lung adenocarcinoma. Cancer Res 2017;77:3040-3056.
[PubMed]
82.
Lord CJ, Ashworth A: BRCAness revisited. Nat Rev Cancer 2016;16:110-120.
[PubMed]
83.
Kamel D, Gray C, Walia JS, Kumar V: PARP inhibitor drugs in the treatment of breast, ovarian, prostate and pancreatic cancers: An update of clinical trials. Curr Drug Targets 2018;19:21-37.
[PubMed]
84.
Rahma OE, Duffy A, Liewehr DJ, et al.: Second-line treatment in advanced pancreatic cancer: A comprehensive analysis of published clinical trials. Ann Oncol 2013;24:1972-1979.
[PubMed]
85.
Assaf E, Verlinde-Carvalho M, Delbaldo C, et al.: 5-Fluorouracil/leucovorin combined with irinotecan and oxaliplatin (FOLFIRINOX) as second-line chemotherapy in patients with metastatic pancreatic adenocarcinoma. Oncology 2011;80:301-306.
[PubMed]
86.
Dietlein F, Thelen L, Jokic M, et al.: A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. Cancer Discov 2014;4:592-605.
[PubMed]
87.
Jiang H, Reinhardt HC, Bartkova J, et al.: The combined status of ATM and p53 link tumor development with therapeutic response. Genes Dev 2009;23:1895-1909.
[PubMed]
88.
Riabinska A, Daheim M, Herter-Sprie GS, et al.: Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci Transl Med 2013;5:189ra78.
[PubMed]
89.
Thijssen R, Ter Burg J, Garrick B, et al.: Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood 2016;128:574-583.
[PubMed]
90.
Gao Y, Chaudhuri J, Zhu C, et al.: A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity 1998;9:367-376.
[PubMed]
91.
Xu Y, Ashley T, Brainerd EE, et al.: Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 1996;10:2411-2422.
[PubMed]
92.
Gurley KE, Kemp CJ: Synthetic lethality between mutation in Atm and DNA-PK(cs) during murine embryogenesis. Curr Biol 2001;11:191-194.
[PubMed]
93.
Landau DA, Tausch E, Taylor-Weiner AN, et al.: Mutations driving CLL and their evolution in progression and relapse. Nature 2015;526:525-530.
[PubMed]
94.
O'Reilly EM, Lee JW, Lowery MA, et al.: Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer 2018;124:1374-1382.
[PubMed]
95.
Lowery MA, Kelsen DP, Capanu M, et al.: Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer 2018;89:19-26.
[PubMed]
© 2018 S. Karger GmbH, Freiburg
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2018
You do not currently have access to this content.
