@article{VermaRaiKaushiketal.2016,
  author    = {Verma, Nidhi and Rai, Amit Kumar and Kaushik, Vibha and Br{\"u}nnert, Daniela and Chahar, Kirti Raj and Pandey, Janmejay and Goyal, Pankaj},
  title     = {Identification of gefitinib off-targets using a structure-based systems biology approach; their validation with reverse docking and retrospective data mining},
  series = {Scientific Reports},
  volume    = {6},
  journal   = {Scientific Reports},
  number    = {33949},
  doi       = {10.1038/srep33949},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-167621},
  year      = {2016},
  abstract  = {Gefitinib, an EGFR tyrosine kinase inhibitor, is used as FDA approved drug in breast cancer and non-small cell lung cancer treatment. However, this drug has certain side effects and complications for which the underlying molecular mechanisms are not well understood. By systems biology based in silico analysis, we identified off-targets of gefitinib that might explain side effects of this drugs. The crystal structure of EGFR-gefitinib complex was used for binding pocket similarity searches on a druggable proteome database (Sc-PDB) by using IsoMIF Finder. The top 128 hits of putative off-targets were validated by reverse docking approach. The results showed that identified off-targets have efficient binding with gefitinib. The identified human specific off-targets were confirmed and further analyzed for their links with biological process and clinical disease pathways using retrospective studies and literature mining, respectively. Noticeably, many of the identified off-targets in this study were reported in previous high-throughput screenings. Interestingly, the present study reveals that gefitinib may have positive effects in reducing brain and bone metastasis, and may be useful in defining novel gefitinib based treatment regime. We propose that a system wide approach could be useful during new drug development and to minimize side effect of the prospective drug.},
  language  = {en}
}
@article{PrietoGarciaHartmannReisslandetal.2022,
  author    = {Prieto-Garcia, Cristian and Hartmann, Oliver and Reissland, Michaela and Braun, Fabian and Bozkurt, S{\"u}leyman and Pahor, Nikolett and Fuss, Carmina and Schirbel, Andreas and Sch{\"u}lein-V{\"o}lk, Christina and Buchberger, Alexander and Calzado Canale, Marco A. and Rosenfeldt, Mathias and Dikic, Ivan and M{\"u}nch, Christian and Diefenbacher, Markus E.},
  title     = {USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K},
  series = {Molecular Oncology},
  volume    = {16},
  journal   = {Molecular Oncology},
  number    = {17},
  doi       = {10.1002/1878-0261.13217},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-312777},
  pages     = {3082-3106},
  year      = {2022},
  abstract  = {Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a 'premalignant' state, and its inhibition synergizes with clinically established compounds used to target EGFR\(^{L858R}\)-, BRAF\(^{V600E}\)- or PI3K\(^{H1047R}\)-driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.},
  language  = {en}
}
@article{LewitzkiAndratschkeKuhntetal.2015,
  author    = {Lewitzki, Victor and Andratschke, Nicolaus and Kuhnt, Thomas and Hildebrandt, Guido},
  title     = {Radiation myelitis after hypofractionated radiotherapy with concomitant gefitinib},
  series = {Radiation Oncology},
  volume    = {10},
  journal   = {Radiation Oncology},
  number    = {29},
  doi       = {10.1186/s13014-015-0334-7},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175443},
  year      = {2015},
  abstract  = {We describe the case of a 71-year-old Caucasian female with primary disseminated non-small cell cancer of the lung, presented for palliative radiotherapy of metastatic spread to the 9th and 11th thoracic vertebrae without intramedullary growth. Palliative radiotherapy with daily fractions of 3 Gy and a cumulative dose of 36 Gy to thoracic vertebrae 8-12 was performed. The patient received concomitantly 250 mg gefitinib daily. After a latent period of 16 months, the patient developed symptoms of myelitis. Magnetic resonance imaging (MRI) did not reveal any bony or intraspinal tumor progression, but spinal cord signal alteration. No response to steroids was achieved. The neurological symptoms were progressive in August 2013 with the right leg being completely plegic. The left leg was incompletely paralyzed. Deep and superficial sensitivity was also diminished bilaterally. The patient was completely urinary and anally incontinent. Contrary to the clinical findings, a follow-up MRI (July 2013) showed amelioration of the former signal alterations in the spinal cord. The diagnosis of paraneoplastic myelopathy was refuted by a negative test for autologous antibodies. At the last clinical visit in May 2014, the neurological symptoms were stable. The last tumor-specific treatment the patient is receiving is erlotinib 125 mg/d. We reviewed the literature and found no reported cases of radiation myelopathy after the treatment in such a setting. The calculated probability of such complication after radiotherapy alone is statistically measurable at the level of 0.02\%. We suppose that gefitinib could also play a role in the development of this rare complication.},
  language  = {en}
}