Genetic Instability & Resistance
Genomic instability represents a hallmark in carcinogenesis and is also intimately linked to cancer therapy, as many conventional treatments, such as ionizing radiation or chemotherapeutics act by means of their DNA-damaging properties. The cancer “mutanome” has been identified as a predictive marker for response in the context of cancer immunotherapy (i.e. checkpoint inhibitor therapy or vaccinations). Research in the field of genomic instability and DNA repair has been a long-standing core area at the UCT (e.g. DFG Research Unit; FOR 527: "Susceptibility factors of tumorigenesis", 2002-2010). Newly appointed investigators (K. Rajalingam, Heisenberg-Professorship; W. Roth, Director of the Institute of Pathology; M. Schmidt, Molecular Signal Transduction Lab) have a strong impact on the program.
- UCT Investigators studied the role of O6-methylguanine-DNA methyltransferase (MGMT) in cancer protection and cancer therapy. They showed that MGMT is a key node in protection against methylating and chloroethylating anticancer drugs causing resistance in gliomas and malignant melanomas (Kaina B. DNA Repair 2007; Naumann S.C. Br. J. Cancer 2009).
- Translational research demonstrated that MGMT promoter hypermethylation correlates with high progression-free survival and overall survival (Christmann M. Int. J. Cancer 2010). Based on these experiments, methylation-specific PCR (MSP) is performed in all glioblastoma patients undergoing surgery in the UCT / Department of Neurosurgery.
- Current studies explore the mode of interaction between genotoxic drugs and tyrosine kinase inhibitors in malignant melanoma (Roos W.P. Oncotarget 2014) and address the question whether defined thresholds for genotoxic carcinogens exist (Fahrer J. Carcinogenesis 2015).
- Targeting aberrant DNA damage response and repair has been shown to induce synthetic vulnerability in KRAS-mutant tumor cells (Kindler T. Blood 2014) suggesting a genotype-specific treatment strategy. In tumor cells, DNA damage induced by replicative stress, increased levels of reactive oxygen species or aberrant DNA repair is counterbalanced by disturbed regulation of apoptotic cell death.
- Investigators explore the role of defined anti-apoptotic pathways and components in drug resistance. Targeting Survivin has been shown to sensitize cancer cells to cytotoxic therapy (Stauber R.H. Hum Mutat. 2013) followed by the subsequent development of small-molecule Survivin export inhibitors (Survexins; European Patent EP 2431364A1; 2015).
- Analysis of alternative types of cell death, such as necroptosis or HMGB1-induced metabolic cell death identified novel therapeutic targets in cancer therapy (Roth W. Cancer Res. 2010; Roth W. Oncogene 2015).
- The interrelationship of IAPs and ubiquitination in cancer is currently analyzed by the Rajalingam group (Rajalingam K. EMBO J. 2014).
- Targeting anticoagulant pathways using specific inhibitors caused modulation of the tumor microenvironment and interrupted tumor promotion (Ruf W. PLos One 2013; Ruf W. Cancer Res. 2008).
- Translational research involves the analysis of predictive gene expression profiles conferring chemosensitivity, which is currently tested in an investigator initiated neoadjuvant phase II clinical trial in breast cancer patients (Schmidt M. EXPRESSION, EudraCT-Nummer: 2008-006381-29).
- UCT Investigators have recently uncovered the mechanisms behind Ubiquitin dependent regulation of RAF, MAPKs and RhoGTPases thus controlling tumor cell shape, migration and differentiation (Dogan T. Nat Cell Biol 2008; Oberoi T.K. EMBOJ 2012; Oberoi-Khanuja T.K. JBC 2012; Takeda A.N. EMBOJ 2014; Rajalingam K. and Dikic I. Cell 2016). Further, in collaboration with Genentech they have characterized novel ERBB3 mutations in human cancers (Jaiswal B.S. Cancer Cell 2013) and identified novel mechanisms driving the activation of MAPK pathway and resistance of RAF inhibitors (Mooz J. Sci Signal 2014).
Within the last two years, substantial expertise has been accumulated in the new UCT program "Genetic Instability & Resistance". The major aim within this core area will be to foster collaborating efforts under the guidance of the UCT, to specifically develop a translational biomarker program and to promote the transfer of already available inhibitors (Survexin; anticoagulant pathway inhibitors) into first-in-man studies.
Most significant publications since 2013
- Imre, G., J. Berthelet, J. Heering, S. Kehrloesser, I.M. Melzer, B.I. Lee, B. Thiede, V. Dotsch, and K. Rajalingam. 2017. Apoptosis inhibitor 5 is an endogenous inhibitor of caspase-2. EMBO Rep. DOI 10.15252/embr.201643744.
- Rajalingam, K. and I. Dikic. 2016. Snapshot: Expanding the ubiquitin code. Cell 164(5):1074.
- Metzig, O., M.D. Fuchs, K.E. Tagscherer, H.J. Gröne, P. Schirmacher, and W. Roth. 2016. Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. Oncogene. 35(26):3399-409.
- Tomicic, M.T., R. Meise, D. Aasland, N. Berte, R. Kitzinger, O.H. Krämer, B. Kaina, and M. Christmann. 2015. Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM. Oncotarget. 6:33755-68.
- Fahrer, J., J. Frisch, G. Nagel, A. Kraus, B. Dörsam, A.D. Thomas, S. Reißig, A. Waisman, and B. Kaina. 2015. DNA repair by MGMT, but not AAG, causes a threshold in alkylation-induced colorectal carcinogenesis. Carcinogenesis. 36:1235-44.
- Mooz, J., T.K. Oberoi-Khanuja, G.S. Harms, W. Wang, B.S. Jaiswal, S. Seshagiri, R. Tikkanen, and K. Rajalingam. 2014. Dimerization of the kinase ARAF promotes MAPK pathway activation and cell migration. Sci Signal. 7(337):ra73.
- Takeda, A.N., T.K. Oberoi-Khanuja, G. Glatz, K. Schulenburg, R.P. Scholz, A. Carpy, B. Macek, A. Remenyi, and K. Rajalingam. 2014. Ubiquitin-dependent regulation of MEKK2/3-MEK5-ERK5 signaling module by XIAP and cIAP1. EMBO J. 233:1784-801.
- Hahnel, P.S., B. Enders, D. Sasca, W.P. Roos, B. Kaina, L. Bullinger, M. Theobald, and T. Kindler. 2014. Targeting components of the alternative NHEJ pathway sensitizes KRAS mutant leukemic cells to chemotherapy. Blood. 123:2355-66.
- Jaiswal, B.S., N.M. Kljavin, E.W. Stawiski, E. Chan, C. Parikh, S. Durinck, S. Chaudhuri, K. Pujara, J. Guillory, K.A. Edgar, V. Janakiraman, R.P. Scholz, K.K. Bowman, M. Lorenzo, H. Li, J. Wu, W. Yuan, B.A. Peters, Z. Kan, J. Stinson, M. Mak, Z. Modrusan, C. Eigenbrot, R. Firestein, H.M. Stern, K. Rajalingam, G. Schaefer, M.A. Merchant, M.X. Sliwkowski, F.J. de Sauvage, and S. Seshagiri. 2013. Oncogenic ERBB3 mutations in human cancers. Cancer Cell 23(5):603-17.
Schaffner, F., N. Yokota, T. Carneiro-Lobo, M. Kitano, M. Schaffer, G.M. Anderson, B.M. Mueller, C.T. Esmon, and W. Ruf. 2013. Endothelial protein C receptor function in murine and human breast cancer development. Plos One. 8:e61071.
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