The Histogenetic Origin of Malignant Cells Predicts Their Susceptibility towards Synthetic Lethality Utilizing the TK.007 System
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The Histogenetic Origin of Malignant Cells Predicts Their Susceptibility towards Synthetic Lethality Utilizing the TK.007 System. / Pallasch, Fabian Bernhard; Freytag, Vera; Kriegs, Malte; Gatzemeier, Dennis; Mair, Thomas; Voss, Hannah; Riecken, Kristoffer; Dawood, Mona; Fehse, Boris; Efferth, Thomas; Schlüter, Hartmut; Schumacher, Udo.
In: CANCERS, Vol. 16, No. 12, 2278, 19.06.2024.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The Histogenetic Origin of Malignant Cells Predicts Their Susceptibility towards Synthetic Lethality Utilizing the TK.007 System
AU - Pallasch, Fabian Bernhard
AU - Freytag, Vera
AU - Kriegs, Malte
AU - Gatzemeier, Dennis
AU - Mair, Thomas
AU - Voss, Hannah
AU - Riecken, Kristoffer
AU - Dawood, Mona
AU - Fehse, Boris
AU - Efferth, Thomas
AU - Schlüter, Hartmut
AU - Schumacher, Udo
PY - 2024/6/19
Y1 - 2024/6/19
N2 - BACKGROUND: Remarkable differences exist in the outcome of systemic cancer therapies. Lymphomas and leukemias generally respond well to systemic chemotherapies, while solid cancers often fail. We engineered different human cancer cells lines to uniformly express a modified herpes simplex virus thymidine kinase TK.007 as a suicide gene when ganciclovir (GCV) is applied, thus in theory achieving a similar response in all cell lines.METHODS: Fifteen different cell lines were engineered to express the TK.007 gene. XTT-cell proliferation assays were performed and the IC50-values were calculated. Functional kinome profiling, mRNA sequencing, and bottom-up proteomics analysis with Ingenuity pathway analysis were performed.RESULTS: GCV potency varied among cell lines, with lymphoma and leukemia cells showing higher susceptibility than solid cancer cells. Functional kinome profiling implies a contribution of the SRC family kinases and decreased overall kinase activity. mRNA sequencing highlighted alterations in the MAPK pathways and bottom-up proteomics showed differences in apoptotic and epithelial junction signaling proteins.CONCLUSIONS: The histogenetic origin of cells influenced the susceptibility of human malignant cells towards cytotoxic agents with leukemias and lymphomas being more sensitive than solid cancer cells.
AB - BACKGROUND: Remarkable differences exist in the outcome of systemic cancer therapies. Lymphomas and leukemias generally respond well to systemic chemotherapies, while solid cancers often fail. We engineered different human cancer cells lines to uniformly express a modified herpes simplex virus thymidine kinase TK.007 as a suicide gene when ganciclovir (GCV) is applied, thus in theory achieving a similar response in all cell lines.METHODS: Fifteen different cell lines were engineered to express the TK.007 gene. XTT-cell proliferation assays were performed and the IC50-values were calculated. Functional kinome profiling, mRNA sequencing, and bottom-up proteomics analysis with Ingenuity pathway analysis were performed.RESULTS: GCV potency varied among cell lines, with lymphoma and leukemia cells showing higher susceptibility than solid cancer cells. Functional kinome profiling implies a contribution of the SRC family kinases and decreased overall kinase activity. mRNA sequencing highlighted alterations in the MAPK pathways and bottom-up proteomics showed differences in apoptotic and epithelial junction signaling proteins.CONCLUSIONS: The histogenetic origin of cells influenced the susceptibility of human malignant cells towards cytotoxic agents with leukemias and lymphomas being more sensitive than solid cancer cells.
U2 - 10.3390/cancers16122278
DO - 10.3390/cancers16122278
M3 - SCORING: Journal article
C2 - 38927982
VL - 16
JO - CANCERS
JF - CANCERS
SN - 2072-6694
IS - 12
M1 - 2278
ER -
