title: Combining targeted drugs to overcome and prevent resistance of solid cancers with some stem-like cell features.
abstract: Treatment resistance significantly inhibits the efficiency of targeted cancer therapies in drug-sensitive genotypes. In the current work, we studied mechanisms for rapidly occurring, adaptive resistance in targeted therapy-sensitive lung, breast, and melanoma cancer cell lines. The results show that in ALK translocated lung cancer lines H3122 and H2228, cells with cancer stem-like cell features characterized by high expression of cancer stem cell markers and/or in vivo tumorigenesis can mediate adaptive resistance to oncogene ablative therapy. When pharmacological ablation of ALK oncogene was accompanied with PI3K inhibitor or salinomycin therapy, cancer stem-like cell features were reversed which was accompanied with decreased colony formation. Furthermore, co-targeting was able to block the formation of acquired resistance in H3122 line. The results suggest that cells with cancer stem-like cell features can mediate adaptive resistance to targeted therapies. Since these cells follow the stochastic model, concurrent therapy with an oncogene ablating agent and a stem-like cell-targeting drug is needed for maximal therapeutic efficiency.
authors.affiliation: Department of Medical Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Jokinen
authors.affiliation: Department of Medical Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Laurila
authors.affiliation: Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine and Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland.
authors.forename: Peppi
authors.initials: P
authors.lastname: Koivunen
authors.affiliation: Department of Medical Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, Oulu, Finland.
authors.forename: Jussi P
authors.initials: JP
authors.lastname: Koivunen
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D061986:MCF-7 Cells; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy*; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011714:Pyrans / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000099295:Formyltetrahydrofolate Dehydrogenase; D000095662:Polyether Polyketides
chemical_list: D000444:Aldehyde Dehydrogenase; D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D000587:Oxidoreductases Acting on CH-NH Group Donors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011714:Pyrans; D020794:Receptor Protein-Tyrosine Kinases; D000099295:Formyltetrahydrofolate Dehydrogenase; C010327:salinomycin; D000095662:Polyether Polyketides; C000626173:ALK protein, human; C000626174:Alk protein, mouse