Center for Molecular Medicine Cologne

Jachimowicz, Ron | Reinhardt, Christian - A 10

Exploring the efficacy of PARP1 inhibition and anti-PD1 treatment for UBQLN4-overexpressing KRAS-driven lung adenocarcinoma

Introduction

We showed that UBQLN4 overexpression significantly co-clusters with KRAS mutations in NSCLC, represses homologous recombination (HR) and is associated with poor survival in NSCLC.

We further showed that HR defects are associated with PARP inhibitor (PARPi) sensitivity. Moreover, HR defects lead to increased mutation frequency. Thus, we will characterize the efficacy of PARPi and immune checkpoint blockade, to provide a rationale for the clinical validation of these experiments in NSCLC patients harboring oncogenic KRAS and UBQLN4 overexpression.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Particularly in lung adenocarcinoma (LuAc, the largest NSCLC subset), the identification of actionable aberrations in kinase genes led to improved patient survival. However, in ~32% of LuAcs, mutated KRAS has been identified, for which no direct targeting approach exists. Further analysis determined loss-of-function alterations in central components of the DNA damage response (DDR), such as in TP53 and ATM, suggesting an impaired DDR may be selected in KRAS-mutant LuAc. Specifically, a defect in homologous recombination (HR) has been associated with a marked sensitivity against PARP1 inhibitors.

 We recently identified UBQLN4 as a master regulator, which represses HR by removing MRE11 from damaged chromatin. Importantly, UBQLN4 overexpression significantly co-clusters with oncogenic KRAS mutations in LuAc.  Moreover, UBQLN4 overexpression is associated with reduced overall survival in LuAc.

With the generation of conditional Ubqln4 knockin mice in combination with autochthonous mouse models of Kras-driven LuAc, we will elucidate the preclinical efficacy of PARP1 inhibitiors (PARPi) in these tumors. We will further flesh out the mechanism of how UBQLN4 is overexpressed in KRAS-mutant LuAc. It is conceivable that HR defects are associated with increased tumor mutational burden, which has been shown to be predictive of favorable response to immune checkpoint inhibitors (ICI) in LuAc. Thus, we will also assess the potential of anti-PD1 treatment in HRR-defective KRAS-mutant LuAcs.

Our Aims

  1. Validate PARP1 inhibitor sensitivity in UBQLN4-overexpressing Kras-driven lung adenocarcinoma in vivo.

  2. Identify the mechanism of UBQLN4 overexpression in Kras-driven lung adenocarcinoma and additional druggable targets in HRR defective settings.

  3. Elucidate the influence of UBQLN4 expression on immunogenicity and immunotherapy with anti-PD-1 antibodies in Kras-driven lung adenocarcinoma.

Previous Work

Genome instability is a hallmark of both, certain human syndromes (so-called genome instability syndromes) and cancer. We recently identified a deleterious UBQLN4 mutation in two consanguineous families with an autosomal recessive syndrome reminiscent of known genome instability disorders. Using cells from the affected individuals, as well as genetically engineered cells, we showed that UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HR).

We demonstrated that loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HR and favors the use of error-prone and mutagenic non-homologous end joining.

Moreover, we found that UBQLN4 is overexpressed in aggressive tumors. In line with an HR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.

  • Brockelmann PJ, de Jong MRW, and Jachimowicz RD (2020). Targeting DNA Repair, Cell Cycle, and Tumor Microenvironment in B Cell Lymphoma. Cells 9.
  • Bendell JC, Bischoff HG, Hwang J, Reinhardt HC, Zander T, Wang X, Hynes S, Pitou C, Campbell R, Iversen P, Farrington DL, Bell-McGuinn K, and Thomas M (2020). A phase 1 dose-escalation study of checkpoint kinase 1 (CHK1) inhibitor prexasertib in combination with p38 mitogen-activated protein kinase (p38 MAPK) inhibitor ralimetinib in patients with advanced or metastatic cancer. Investigational new drugs 38, 1145-55.
  • Flumann R, Nieper P, Reinhardt HC, and Knittel G (2020). New murine models of aggressive lymphoma. Leuk Lymphoma 61, 788-98.
  • Jakobs F, Drost R, Kron A, Heinen J, Hallek M, Reinhardt HC, Zander T, and Kron F (2020). Economic Impact of the Introduction of Outpatient Medical Specialist Care (ASV) of Gastrointestinal Cancer Patients from a German Hospital Management Perspective. Oncol Res Treat 43, 498-505.
  • 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, and Nguyen PH (2020). Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Emicro-TCL1 Transgenic Mouse Model. Cancers (Basel) 12.
  • Kong YW, Dreaden EC, Morandell S, Zhou W, Dhara SS, Sriram G, Lam FC, Patterson JC, Quadir M, Dinh A, Shopsowitz KE, Varmeh S, Yilmaz OH, Lippard SJ, Reinhardt HC, Hemann MT, Hammond PT, and Yaffe MB (2020). Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints. Nat Commun 11, 4124.
  • Kreuzer KA, Furman RR, Stilgenbauer S, Dubowy RL, Kim Y, Munugalavadla V, Lilienweiss E, Reinhardt HC, Cramer P, Eichhorst B, Hillmen P, O'Brien SM, Pettitt AR, and Hallek M (2020). The impact of complex karyotype on the overall survival of patients with relapsed chronic lymphocytic leukemia treated with idelalisib plus rituximab. Leukemia 34, 296-300.
  • 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, Wossmann W, Borkhardt A, Burdach S, Hansmann ML, Rosenwald A, Perner S, Mall G, Klapper W, Merseburg A, Kruger M, Grull H, Persigehl T, Wunderlich FT, Peifer M, Utermohlen O, Buttner R, Beleggia F, and Reinhardt HC (2020). ATM activity in T cells is critical for immune surveillance of lymphoma in vivo. Leukemia 34, 771-86.
  • Spiro JE, Rinneburger M, Hedderich DM, Jokic M, Reinhardt HC, Maintz D, Palmowski M, and Persigehl T (2020). Monitoring treatment effects in lung cancer-bearing mice: clinical CT and clinical MRI compared to micro-CT. Eur Radiol Exp 4, 31.
  • Volz C, Breid S, Selenz C, Zaplatina A, Golfmann K, Meder L, Dietlein F, Borchmann S, Chatterjee S, Siobal M, Schottle J, Florin A, Koker M, Nill M, Ozretic L, Uhlenbrock N, Smith S, Buttner R, Miao H, Wang B, Reinhardt HC, Rauh D, Hallek M, Acker-Palmer A, Heukamp LC, and Ullrich RT (2020). Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC. Cell Rep 31, 107568.
Dr. Ron Jachimowicz CMMC Cologne
Dr. Ron Jachimowicz

Clinic I of Internal Medicine & MPI of Ageing

CMMC - PI - A 10

+ 49 221 37 970 580

Clinic I of Internal Medicine & MPI of Ageing

Cologne Center for Genomics University of Cologne Weyertal 115 b

50931 Cologne

https://www.age.mpg.de/science/research-laboratories/jachimowicz/cv

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Prof. H Christian Reinhardt CMMC Cologne
Prof. H Christian Reinhardt

Clinic for Hematology - Essen University Hospital

CMMC - former PI - A 10

0201 723-3136

0201 723-5961

Clinic for Hematology - Essen University Hospital

present adress: Universitätsklinikum Essen (AöR) Hufelandstraße 55

45147 Essen

http://reinhardt.cecad-labs.uni-koeln.de/Lab-Members.637.0.html

CMMC Profile Page

Curriculum Vitae (CV)

Publications on PubMed

Publications - H Christian Reinhardt

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