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Cells
Volume 9
Issue 9
10.3390/cells9092110
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Article

Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy

by
Elodie Roger
1,†,
Johann Gout
1,†,
Frank Arnold
1,
Alica K. Beutel
1,
Martin Müller
1,
Alireza Abaei
2,
Thomas F. E. Barth
3,
Volker Rasche
2,
Thomas Seufferlein
1,
Lukas Perkhofer
1,* and
Alexander Kleger
1,*
1
Department of Internal Medicine 1, University Medical Center Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany
2
Center for Translational Imaging (MoMAN), Ulm University, 89081 Ulm, Germany
3
Institute of Pathology, University Medical Center Ulm, 89081 Ulm, Germany
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2020, 9(9), 2110; https://doi.org/10.3390/cells9092110
Received: 25 August 2020 / Revised: 11 September 2020 / Accepted: 14 September 2020 / Published: 16 September 2020
(This article belongs to the Special Issue Genome Dynamics in Pancreatic Cancer Biology and Therapy)
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Abstract

Personalized medicine in treating pancreatic ductal adenocarcinoma (PDAC) is still in its infancy, albeit PDAC-related deaths are projected to rise over the next decade. Only recently, maintenance therapy with the PARP inhibitor olaparib showed improved progression-free survival in germline BRCA1/2-mutated PDAC patients after platinum-based induction for the first time. Transferability of such a concept to other DNA damage response (DDR) genes remains unclear. Here, we conducted a placebo-controlled, three-armed preclinical trial to evaluate the efficacy of multi-DDR interference (mDDRi) as maintenance therapy vs. continuous FOLFIRINOX treatment, implemented with orthotopically transplanted ATM-deficient PDAC cell lines. Kaplan–Meier analysis, cross-sectional imaging, histology, and in vitro analysis served as analytical readouts. Median overall survival was significantly longer in the mDDRi maintenance arm compared to the maintained FOLFIRINOX treatment. This survival benefit was mirrored in the highest DNA-damage load, accompanied by superior disease control and reduced metastatic burden. In vitro analysis suggests FOLFIRINOX-driven selection of invasive subclones, erased by subsequent mDDRi treatment. Collectively, this preclinical trial substantiates mDDRi in a maintenance setting as a novel therapeutic option and extends the concept to non-germline BRCA1/2-mutant PDAC. View Full-Text
Keywords: pancreatic ductal adenocarcinoma; ATM; chromosomal instability; targeted therapy; DNA damage repair; platinum; PARP; maintenance therapy pancreatic ductal adenocarcinoma; ATM; chromosomal instability; targeted therapy; DNA damage repair; platinum; PARP; maintenance therapy
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MDPI and ACS Style

Roger, E.; Gout, J.; Arnold, F.; Beutel, A.K.; Müller, M.; Abaei, A.; Barth, T.F.E.; Rasche, V.; Seufferlein, T.; Perkhofer, L.; Kleger, A. Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy. Cells 2020, 9, 2110. https://doi.org/10.3390/cells9092110

AMA Style

Roger E, Gout J, Arnold F, Beutel AK, Müller M, Abaei A, Barth TFE, Rasche V, Seufferlein T, Perkhofer L, Kleger A. Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy. Cells. 2020; 9(9):2110. https://doi.org/10.3390/cells9092110

Chicago/Turabian Style

Roger, Elodie, Johann Gout, Frank Arnold, Alica K. Beutel, Martin Müller, Alireza Abaei, Thomas F.E. Barth, Volker Rasche, Thomas Seufferlein, Lukas Perkhofer, and Alexander Kleger. 2020. "Maintenance Therapy for ATM-Deficient Pancreatic Cancer by Multiple DNA Damage Response Interferences after Platinum-Based Chemotherapy" Cells 9, no. 9: 2110. https://doi.org/10.3390/cells9092110

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