The Histogenetic Origin of Malignant Cells Predicts Their Susceptibility towards Synthetic Lethality Utilizing the TK.007 System

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...

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Published in:	Cancers Vol. 16; no. 12; p. 2278
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 19-06-2024 MDPI
Subjects:	Amino acids Apoptosis Calibration Cancer therapies Cell growth Cell proliferation Cytotoxic agents Cytotoxicity Disease susceptibility Ethylenediaminetetraacetic acid Ganciclovir Hematology Herpes simplex Herpes viruses Kinases Lethality Leukemia Lymphoma Lymphomas MAP kinase Melanoma mRNA Osteosarcoma Penicillin Peptides Proteins Proteomics Risk factors RNA RNA sequencing Suicide genes Susceptibility Thymidine kinase Tumor cell lines Germany United Kingdom > UK United States > US suicide gene transduction functional kinome profiling drug resistance ganciclovir herpes simplex virus thymidine kinase chemotherapy
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Summary:	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. Fifteen different cell lines were engineered to express the gene. XTT-cell proliferation assays were performed and the IC -values were calculated. Functional kinome profiling, mRNA sequencing, and bottom-up proteomics analysis with Ingenuity pathway analysis were performed. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2072-6694 2072-6694
DOI:	10.3390/cancers16122278