A new approach to overcoming anticancer drug resistance
Posted by Leanne Kodsman on
New research shows a new method for overcoming drug-resistance in cancer cells. Cells with acquired (de novo) resistance to kinase inhibitors characteristically show increased numbers of and/or longer cilia. Blocking cilia growth, the study illustrates, resensitizes the cells to anticancer drugs.
Scientists in the UK have shown that targeting the cilia of cancer cells could be a universal way to make resistant cancer cells sensitive to anticancer drugs. The recent study looks at the characteristics of resistant cancer cells, noting that cells with either acquired or de novo resistance to traditional kinase inhibitors have either increased quantities of and/or notably longer cilia. By blocking cilia growth or signaling, the cancer cells become receptive to anticancer drugs. On the flip side, increasing the length of cilia made previously drug-receptive cells become resistant to kinase inhibitors. Researchers hope that targeting cilia could be a way to universally strip cancer cells of their innate defenses, making treatments more effective.
Cilia and Drug Resistance
Many anticancer drugs inhibit proteins like epidermal growth factor receptor, platelet-derived growth factor receptor, and KRAS. While treatment with kinase inhibitors (like erlotinib) can be effective for some tumor types, it seems as though drug resistance eventually emerges.
With the link association between oncogenic proteins and cilia, the researchers wanted to discover whether changes in ciliogenesis could play a permissive role of sorts in the development of drug resistance, and wanted to test whether the characteristics of cilia (like number and length) would affect resistance to kinase inhibitors in different cell lines (including lung cancer and sarcoma cells).
Relationship between de novo drug resistance and ciliogenisis confirmed
Initial studies found that drug-resistant cancer cells showed greater numbers of and/or longer length of cilia. Downregulating the protein Kif7 (known to be involved in controlling cilia length) led to developing resistance to dasatinib, an anticancer drug, in cells that were previously sensitive to the drug. Blocking ciliogenesis by knocking down a structural protein or chemically inhibiting the Hedgehog pathway resensitized cancer cells to kinase inhibitor therapy.
The team was able to confirm an association between de novo drug resistance and ciliogenesis, and demonstrated that using a chemical FGFR inhibitor lead to increased cancer cell death when the cells were then exposed to a kinase inhibitor.
Further research will explore cilia changes in greater detail, with the goal of gaining more understanding of how they impact resistance to cancer drug therapies, and how they could be targeted to increase the effectiveness of treatment.
Further Reading & References:
Targeting Cilia Could Offer Universal Approach to Combat Anticancer Drug Resistance. GEN: Genetic Engineering & Biotechnology News. 06 June 2018.
Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer. Cell Reports: Volume 23, Issue 10, p3042-3055, 5 June 2018.
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