title: Biological and molecular effects of small molecule kinase inhibitors on low-passage human colorectal cancer cell lines.
abstract: Low-passage cancer cell lines are versatile tools to study tumor cell biology. Here, we have employed four such cell lines, established from primary tumors of colorectal cancer (CRC) patients, to evaluate effects of the small molecule kinase inhibitors (SMI) vemurafenib, trametinib, perifosine, and regorafenib in an in vitro setting. The mutant BRAF (V600E/V600K) inhibitor vemurafenib, but also the MEK1/2 inhibitor trametinib efficiently inhibited DNA synthesis, signaling through ERK1/2 and expression of genes downstream of ERK1/2 in BRAF mutant cells only. In case of the AKT inhibitor perifosine, three cell lines showed a high or intermediate responsiveness to the drug while one cell line was resistant. The multikinase inhibitor regorafenib inhibited proliferation of all CRC lines with similar efficiency and independent of the presence or absence of KRAS, BRAF, PIK3CA, and TP53 mutations. Regorafenib action was associated with broad-range inhibitory effects at the level of gene expression but not with a general inhibition of AKT or MEK/ERK signaling. In vemurafenib-sensitive cells, the antiproliferative effect of vemurafenib was enhanced by the other SMI. Together, our results provide insights into the determinants of SMI efficiencies in CRC cells and encourage the further use of low-passage CRC cell lines as preclinical models.
authors.affiliation: Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany ; Oscar Langendorff Institute of Physiology, Rostock University Medical Center, Gertrudenstraße 9, 18057 Rostock, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Lange
authors.affiliation: Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Franz
authors.affiliation: Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Maletzki
authors.affiliation: Molecular Oncology and Immunotherapy, Department of General Surgery, Rostock University Medical Center, Schillingallee 35, 18057 Rostock, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Linnebacher
authors.affiliation: Institute of Pathology, Rostock University Medical Center, Strempelstraße 14, 18055 Rostock, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Hühns
authors.affiliation: Department of Medicine II, Division of Gastroenterology, Rostock University Medical Center, Ernst-Heydemann-Straße 6, 18057 Rostock, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Jaster
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001973:Bromodeoxyuridine / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D052138:Genes, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000235:genetics; D054852:Small Molecule Libraries / Q000494:pharmacology*
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D001973:Bromodeoxyuridine