Initiation of High Frequency Multi-Drug Resistance Following Kinase Targeting by siRNAs

Charles Swanton, Barbara Nicke, Michela Marani, Gavin Kelly and Julian Downward

volume 6 | issue 16

15 August 2007
Pages: 2001 - 2004

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The sequential use of non-cross resistant cytotoxic agents is the standard of care for advanced solid tumours in order to enhance survival and optimise quality of life. Nevertheless, drug resistance to non cross-resistant agents is commonly witnessed, with clinical response rates to “non cross-resistant” regimens declining as the disease advances. Expression of ABC transporters is unlikely to fully explain this phenomenon, and a clear molecular explanation for this process remains uncertain. A statistical analysis of a recently published RNA interference screen targeting 779 kinases in three cell lines deriving from different tumour types reveals a significant correlation between resistance to paclitaxel and a “non cross-resistant” cytotoxic agent. Furthermore, 20% of kinases that promote resistance to paclitaxel when targeted by RNAi also promote resistance to a non cross-resistant agent within that same cell line, consistent with a tissue-type dependence of multi-drug resistance. Conversely, paclitaxel-specific resistance and sensitising kinases occur less frequently than expected. This indicates that several cell line specific kinases may regulate multi-drug resistance and provide a potential explanation for the phenomenon of drug resistance to non cross-resistant agents witnessed in oncology practice. Furthermore, this work supports efforts to identify common pathways of drug response for future drug discovery programmes.