Combining targeted drugs to overcome and prevent resistance of solid cancers with some stem-like cell features
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Elina Jokinen1,*, Niina Laurila1,*, Peppi Koivunen2 and Jussi P. Koivunen1
1 Department of Medical Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, Oulu, Finland
2 Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine and Oulu Center for Cell-Matrix Research, University of Oulu, Oulu, Finland
* These authors contributed equally to this work
Jussi Koivunen, email:
Keywords: Targeted cancer therapy, resistance, cancer stem-like cells, non-small cell lung cancer
Received: May 26, 2014 Accepted: September 02, 2014 Published: September 02, 2014
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.
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