TY  - JOUR
A1  - Prieto-Garcia, Cristian
A1  - Tomašković, Ines
A1  - Shah, Varun Jayeshkumar
A1  - Dikic, Ivan
A1  - Diefenbacher, Markus
T1  - USP28: oncogene or tumor suppressor? a unifying paradigm for squamous cell carcinoma
JF  - Cells
N2  - Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.
KW  - USP28
KW  - SCC
KW  - USP25
KW  - FBXW7
KW  - Tp63
KW  - c-MYC
KW  - ΔNp63
KW  - p53
KW  - cancer
KW  - DUB inhibitor
KW  - squamous
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-248409
SN  - 2073-4409
VL  - 10
IS  - 10
ER  - 
TY  - JOUR
A1  - Fischer, Thomas
A1  - Hartmann, Oliver
A1  - Reissland, Michaela
A1  - Prieto-Garcia, Cristian
A1  - Klann, Kevin
A1  - Pahor, Nikolett
A1  - Schülein-Völk, Christina
A1  - Baluapuri, Apoorva
A1  - Polat, Bülent
A1  - Abazari, Arya
A1  - Gerhard-Hartmann, Elena
A1  - Kopp, Hans-Georg
A1  - Essmann, Frank
A1  - Rosenfeldt, Mathias
A1  - Münch, Christian
A1  - Flentje, Michael
A1  - Diefenbacher, Markus E.
T1  - PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy
JF  - Cell & Bioscience
N2  - Background
Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy.

Results
We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model.

Conclusion
PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.
KW  - PTEN
KW  - ATM
KW  - IR
KW  - NSCLC
KW  - radiotherapy
KW  - cancer
KW  - DNA-PK
KW  - PI3K
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-299865
SN  - 2045-3701
VL  - 12
ER  -