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  - 
TY  - JOUR
A1  - Haydn, Johannes M.
A1  - Hufnagel, Anita
A1  - Grimm, Johannes
A1  - Maurus, Katja
A1  - Schartl, Manfred
A1  - Meierjohann, Svenja
T1  - The MAPK pathway as an apoptosis enhancer in melanoma
JF  - Oncotarget
N2  - Inhibition of RAF/MEK/ERK signaling is beneficial for many patients with BRAFV600E–mutated melanoma. However, primary and secondary resistances restrict long-lasting therapy success. Combination therapies are therefore urgently needed. Here, we evaluate the cellular effect of combining a MEK inhibitor with a genotoxic apoptosis inducer. Strikingly, we observed that an activated MAPK pathway promotes in several melanoma cell lines the pro-apoptotic response to genotoxic stress, and MEK inhibition reduces intrinsic apoptosis. This goes along with MEK inhibitor induced increased RAS and P-AKT levels. The protective effect of the MEK inhibitor depends on PI3K signaling, which prevents the induction of pro-apoptotic PUMA that mediates apoptosis after DNA damage. We could show that the MEK inhibitor dependent feedback loop is enabled by several factors, including EGF receptor and members of the SPRED family. The simultaneous knockdown of SPRED1 and SPRED2 mimicked the effects of MEK inhibitor such as PUMA repression and protection from apoptosis. Our data demonstrate that MEK inhibition of BRAFV600E-positive melanoma cells can protect from genotoxic stress, thereby achieving the opposite of the intended anti-tumorigenic effect of the combination of MEK inhibitor with inducers of intrinsic apoptosis.
KW  - PI3K
KW  - melanoma
KW  - RAS
KW  - chemotherapy resistance
KW  - crosstalk
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-120649
SN  - 1949-2553
VL  - 5
IS  - 13
ER  -