Development of synergistic combination regimens for the treatment of chemotherapy-resistant high-risk CLL
Final Report Abstract
During the last seven years, we have witnessed a paradigm shift in our clinical approach to CLL. The advent of novel, highly effective targeted therapeutic molecules, such as the BTK inhibitor ibrutinib, the PI3Kdelta inhibitor idelalisib or the BCL2 inhibitor venetoclax has fundamentally altered our therapeutic algorithms. Despite the undisputed clinical efficacy of the novel compounds, TP53 mutations and alterations on 17p appear to retain their adverse prognostic impact. In addition, inappropriate NFkB activity, as well as oncogenic KRAS mutations and leukemia cell-specific defects in genome maintenance and DNA repair, are emerging as potent novel predictors for adverse therapeutic response in CLL patients. Thus, the molecularly-defined spectrum of CLL cases that display an adverse prognosis, is currently being redefined through the availability of deep genomic sequencing data and the introduction of novel therapeutic agents. In the context of this CRU-286, we bundled our pharmacogenomic screening expertise and our arsenal of novel genetically-engineered mouse models of CLL to specifically focus on these newly defined high-risk CLL cases, in order to uncover novel molecular vulnerabilities specifically in this class of CLL cases. A particular focus was placed on ATM-deficient CLLs and the role of ATM in leukemogenesis and maintenance of the malignant state. Throughout the course of this CRU, we made a number of discoveries centered around targeting malignant cells that harbor well-defined defects in genome maintenance pathways, as well as oncogenic lesions that are associated with functional defects in genome maintenance. First, we generated a series of mouse models harboring various distinct malignant lesions, including CLL, lung cancer and pancreatic ductal adenocarcinoma. We employed these murine models as preclinical avatars, to demonstrate that Atm deficiency is associated with selective sensitivity against PARP1-, ATR- and DNA-PKcs inhibitors. Moreover, we could show that oncogenic Kras mutations induce endogenous genotoxic damage in affected cells. This tonic endogenous genotoxic stress created an actionable molecular dependence on the cell cycle checkpoint kinases CHK1 and MK2. We could show that inhibitors targeting these two kinases display synergistic cytotoxicity in Kras-mutant malignancies. Extending these observations, we could also show that combined inhibition of the ATR/CHK1 axis and the glucose transporter GLUT1 displays synergistic cytotoxicity in Kras-mutant cells and tumors. We also placed a specific emphasis on understanding the biological role of ATM in leukemogenesis and maintenance of the malignant state. One central observation within the second funding period was the discovery that ATM directly phosphorylates the proteasome shuttle factor UBQLN4 on Ser-318. This phosphorylation was critical for UBQLN4 to repress homologous recombination via removal of MRE11 from the damaged chromatin. Lastly, we could show that the continued absence of ATM in lymphoma cells, but also in lymphomainfiltrating T cells is critical to maintain B-NHL lymphomas, in vivo. Altogether, the work within the framework of the CRU-286 led us to a series of new discoveries, which we continue to build new research projects on.
Publications
- Therapeutic targeting of a robust non-oncogene addiction to PRKDC in ATM-defective tumors. Sci Transl Med. 2013 Jun 12;5(189):189ra78
Riabinska A, Daheim M, Herter-Sprie GS, Winkler J, Fritz C, Hallek M, Thomas RK, Kreuzer KA, Frenzel LP, Monfared P, Martins-Boucas J, Chen S, Reinhardt HC
(See online at https://doi.org/10.1126/scitranslmed.3005814) - A functional cancer genomics screen identifies a druggable synthetic lethal interaction between MSH3 and PRKDC. Cancer Discov. 2014 May;4(5):592-605
Dietlein F, Thelen L, Jokic M, Jachimowicz RD, Ivan L, Knittel G, Leeser U, van Oers J, Edelmann W, Heukamp LC, Reinhardt HC
(See online at https://doi.org/10.1158/2159-8290.cd-13-0907) - A Synergistic Interaction between Chk1- and MK2 Inhibitors in KRAS-Mutant Cancer. Cell. 2015 Jul 2;162(1):146-59. Erratum in: Cell. 2015 Aug 27;162(5):1169
Dietlein F, Kalb B, Jokic M, Noll EM, Strong A, Tharun L, Ozretić L, Künstlinger H, Kambartel K, Randerath WJ, Jüngst C, Schmitt A, Torgovnick A, Richters A, Rauh D, Siedek F, Persigehl T, Mauch C, Bartkova J, Bradley A, Sprick MR, Trumpp A, Rad R, Saur D, Bartek J, Wolf J, Büttner R, Thomas RK, Reinhardt HC
(See online at https://doi.org/10.1016/j.cell.2015.05.053) - Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia. Leukemia. 2015 Apr;29(4):981-4
Huelsemann MF, Patz M, Beckmann L, Brinkmann K, Otto T, Fandrey J, Becker HJ, Theurich S, von Bergwelt-Baildon M, Pallasch CP, Zahedi RP, Kashkar H, Reinhardt HC, Hallek M, Wendtner CM, Frenzel LP
(See online at https://doi.org/10.1038/leu.2014.320) - B-cellspecific conditional expression of Myd88p.L252P leads to the development of diffuse large B-cell lymphoma in mice. Blood. 2016 Jun 2;127(22):2732-41
Knittel G, Liedgens P, Korovkina D, Seeger JM, Al-Baldawi Y, Al-Maarri M, Fritz C, Vlantis K, Bezhanova S, Scheel AH, Wolz OO, Reimann M, Möller P, López C, Schlesner M, Lohneis P, Weber AN, Trümper L; German International Cancer Genome Consortium Molecular Mechanisms in Malignant Lymphoma by Sequencing Project Consortium, Staudt LM, Ortmann M, Pasparakis M, Siebert R, Schmitt CA, Klatt AR, Wunderlich FT, Schäfer SC, Persigehl T, Montesinos-Rongen M, Odenthal M, Büttner R, Frenzel LP, Kashkar H, Reinhardt HC
(See online at https://doi.org/10.1182/blood-2015-11-684183) - Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia. Blood. 2016 Jul 28;128(4):574-83
Thijssen R, Ter Burg J, Garrick B, van Bochove GG, Brown JR, Fernandes SM, Rodríguez MS, Michot JM, Hallek M, Eichhorst B, Reinhardt HC, Bendell J, Derks IA, van Kampen RJ, Hege K, Kersten MJ, Trowe T, Filvaroff EH, Eldering E, Kater AP
(See online at https://doi.org/10.1182/blood-2016-02-700328) - ATM Deficiency Is Associated with Sensitivity to PARP1- and ATR Inhibitors in Lung Adenocarcinoma. Cancer Res. 2017 Jun 1;77(11):3040-3056
Schmitt A, Knittel G, Welcker D, Yang TP, George J, Nowak M, Leeser U, Büttner R, Perner S, Peifer M, Reinhardt HC
(See online at https://doi.org/10.1158/0008-5472.can-16-3398) - Two mouse models reveal an actionable PARP1 dependence in aggressive chronic lymphocytic leukemia. Nat Commun. 2017 Jul 28;8(1):153
Knittel G, Rehkämper T, Korovkina D, Liedgens P, Fritz C, Torgovnick A, Al-Baldawi Y, Al- Maarri M, Cun Y, Fedorchenko O, Riabinska A, Beleggia F, Nguyen PH, Wunderlich FT, Ortmann M, Montesinos-Rongen M, Tausch E, Stilgenbauer S, P Frenzel L, Herling M, Herling C, Bahlo J, Hallek M, Peifer M, Buettner R, Persigehl T, Reinhardt HC
(See online at https://doi.org/10.1038/s41467-017-00210-6) - Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun. 2018 Feb 20;9(1):727
Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, Merkel O, Cartolano M, Oberbeck S, Mayer P, Berg V, Thomalla D, Kutsch N, Stiefelhagen M, Cramer P, Wendtner CM, Persigehl T, Saleh A, Altmüller J, Nürnberg P, Pallasch C, Achter V, Lang U, Eichhorst B, Castiglione R, Schäfer SC, Büttner R, Kreuzer KA, Reinhardt HC, Hallek M, Frenzel LP, Peifer M
(See online at https://doi.org/10.1038/s41467-018-03170-7) - The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression. Cell Reports. 2018 Oct 23;25(4):1027-1039.e6
Torgovnick A, Heger JM, Liaki V, Isensee J, Schmitt A, Knittel G, Riabinska A, Beleggia F, Laurien L, Leeser U, Jüngst C, Siedek F, Vogel W, Klümper N, Nolte H, Wittersheim M, Tharun L, Castiglione R, Krüger M, Schauss A, Perner S, Pasparakis M, Büttner R, Persigehl T, Hucho T, Herter-Sprie GS, Schumacher B, Reinhardt HC
(See online at https://doi.org/10.1016/j.celrep.2018.09.079) - UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors. Cell. 2019 Jan 24;176(3):505-519.e22
Jachimowicz RD, Beleggia F, Isensee J, Velpula BB, Goergens J, Bustos MA, Doll MA, Shenoy A, Checa-Rodriguez C, Wiederstein JL, Baranes-Bachar K, Bartenhagen C, Hertwig F, Teper N, Nishi T, Schmitt A, Distelmaier F, Lüdecke HJ, Albrecht B, Krüger M, Schumacher B, Geiger T, Hoon DSB, Huertas P, Fischer M, Hucho T, Peifer M, Ziv Y, Reinhardt HC, Wieczorek D, Shiloh Y
(See online at https://doi.org/10.1016/j.cell.2018.11.024) - ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia. 2020 Mar;34(3):771-786
Riabinska A, Lehrmann D, Jachimowicz RD, Knittel G, Fritz C, Schmitt A, Geyer A, Heneweer C, Wittersheim M, Frenzel LP, Torgovnick A, Wiederstein JL, Wunderlich CM, Ortmann M, Paillard A, Wößmann W, Borkhardt A, Burdach S, Hansmann ML, Rosenwald A, Perner S, Mall G, Klapper W, Merseburg A, Krüger M, Grüll H, Persigehl T, Wunderlich FT, Peifer M, Utermöhlen O, Büttner R, Beleggia F, Reinhardt HC
(See online at https://doi.org/10.1038/s41375-019-0618-2) - Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model. Cancers (Basel). 2020 Jul 20;12(7):1980
Koch M, Reinartz S, Saggau J, Knittel G, Rosen N, Fedorchenko O, Thelen L, Barthel R, Reinart N, Seeger-Nukpezah T, Reinhardt HC, Hallek M, Nguyen PH
(See online at https://doi.org/10.3390/cancers12071980) - Active Akt signaling triggers CLL towards Richter's transformation via over-activation of Notch1. Blood, 2021 Feb 4;137(5):646-660
Kohlhaas V, Blakemore SJ, Al-Maarri M, Nickel N, Pal M, Roth A, Hövelmeyer N, Schäfer SC, Knittel G, Lohneis P, Nikolic M, Wiederstein JL, Reinart N, Herling M, Herling C, Hartmann EM, Rosenwald A, Klapper W, Büttner R, Moia R, Rossi D, Boldorini R, Gaidano G, Frenzel LP, Reinhardt HC, Brüning JC, Hallek M, Krüger M, Peifer M, Pallasch CP, Wunderlich FT
(See online at https://doi.org/10.1182/blood.2020005734)
