TY  - JOUR
A1  - Weißbach, Susann
A1  - Heredia-Guerrero, Sofia Catalina
A1  - Barnsteiner, Stefanie
A1  - Großhans, Lukas
A1  - Bodem, Jochen
A1  - Starz, Hanna
A1  - Langer, Christian
A1  - Appenzeller, Silke
A1  - Knop, Stefan
A1  - Steinbrunn, Torsten
A1  - Rost, Simone
A1  - Einsele, Hermann
A1  - Bargou, Ralf Christian
A1  - Rosenwald, Andreas
A1  - Stühmer, Thorsten
A1  - Leich, Ellen
T1  - Exon-4 Mutations in KRAS Affect MEK/ERK and PI3K/AKT Signaling in Human Multiple Myeloma Cell Lines
JF  - Cancers
N2  - Approximately 20% of multiple myeloma (MM) cases harbor a point mutation in KRAS. However, there is still no final consent on whether KRAS-mutations are associated with disease outcome. Specifically, no data exist on whether KRAS-mutations have an impact on survival of MM patients at diagnosis in the era of novel agents. Direct blockade of KRAS for therapeutic purposes is mostly impossible, but recently a mutation-specific covalent inhibitor targeting KRAS\(^{p.G12C}\) entered into clinical trials. However, other KRAS hotspot-mutations exist in MM patients, including the less common exon-4 mutations. For the current study, the coding regions of KRAS were deep-sequenced in 80 newly diagnosed MM patients, uniformely treated with three cycles of bortezomib plus dexamethasone and cyclophosphamide (VCD)-induction, followed by high-dose chemotherapy and autologous stem cell transplantation. Moreover, the functional impact of KRAS\(^{p.G12A}\) and the exon-4 mutations p.A146T and p.A146V on different survival pathways was investigated. Specifically, KRAS\(^{WT}\), KRAS\(^{p.G12A}\), KRAS\(^{p.A146T}\), and KRAS\(^{p.A146V}\) were overexpressed in HEK293 cells and the KRAS\(^{WT}\) MM cell lines JJN3 and OPM2 using lentiviral transduction and the Sleeping Beauty vector system. Even though KRAS-mutations were not correlated with survival, all KRAS-mutants were found capable of potentially activating MEK/ERK- and sustaining PI3K/AKT-signaling in MM cells.
KW  - multiple myeloma
KW  - KRAS
KW  - MEK/ERK-signaling
KW  - AKT-signaling
KW  - amplicon sequencing
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200617
SN  - 2072-6694
VL  - 12
IS  - 2
ER  -