Targeting Cilia Could Offer Universal Approach to Combat Anticancer Drug Resistance

Scientists in the U.K. have identified a potentially universal way to resensitize drug-resistant cancer cells to therapy, by targeting the cells’ cilia. The Institute of Cancer Research (ICR) team found that cells with either acquired or de novo resistance to kinase inhibitors are characterized by increased numbers and/or longer cilia. Their studies showed that blocking cilia growth—ciliogenesis—or signaling was enough to resensitize the cells to the anticancer drugs. Coversely, increasing cilia length rendered previously drug-sensitive cancer cells resistant to kinase inhibitors.

“We found that small, antenna-like cell structures called cilia play a key role as cancer cells develop resistance to treatment,” comments study leader Barbara Tanos, Ph.D., ICR Fellow in Cancer Therapeutics. “We believe that cilia could help cancer cells become resistant to a wide range of drugs—and therefore that targeting cilia could be a universal way of stripping cancers of their defenses.”

The researchers report their findings in Cell Reports, in a paper entitled “Primary Cilia Mediate Diverse Kinase Inhibitor Resistance Mechanisms in Cancer.”

Primary cilia are sensory structures that are found on nearly all vertebrate cells, but prior studies have suggested opposing roles for cilia in cancer, suggesting that their actual role may be context dependent, the authors note. “Although loss of cilia has been associated with the onset of malignancy in some human  tumors, in others, cilia appear to be necessary for cancer cell survival. In fact,  depending on the nature of the driver oncogenic lesion, cilia can have opposing roles in tumorigenesis even in the same tumor type.”

Interestingly, a number of anticancer drugs inhibit proteins, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), and KRAS, localize to cilia. The nature of the driver oncogenic lesion, for example, is an EGFR inhibitor that binds to the tyrosine kinase domain on the EGFR protein, and while treatment with kinase inhibitors such as erlotinib can be very effective in some tumor types, drug-resistance “invariably” emerges.

Given the link association of oncogenic proteins with cilia, the ICR team hypothesized that changes in ciliogenesis could play “a permissive role” in the emergence of drug resistance. They investigated whether cilia characteristics—including number and length—affected resistance to kinase inhibitors in different cell lines, including lung cancer and sarcoma cells, and evaluated the effects of targeting cilia on drug resistance.

Initial studies in five different cancer cell lines with acquired tyrosine kinase inhibitor resistance found that in each case the cell line exhibited increased numbers of cilia and/or cilia length. A protein known as Kif7 is known to be involved in controlling cilia length, and tests showed that downregulating the protein in cancer cells led to development of resistance to the anticancer drug dasatinib in cells that were normally sensitive to the drug.

Drug resistance is often linked with changes in the activation of signaling pathways, a number of which are either sited in, or controlled by cilia, and the authors reasoned that the drug resistance-related changes in cilia would cause misregulated cilia-dependent signaling. When they looked at this more closely, they identified increased Hedgehog pathway activation in two different types of cancer cell line with acquired tyrosine kinase inhibitor resistance.

“Our results indicate that acquired resistance to kinase inhibitors is associated with the upregulation of a number of ciliogenesis pathways, and suggest that targeting cilia might be an effective strategy to overcome resistance,” the authors write.

They next showed that blocking ciliogenesis either by knocking down a key structural protein, or chemically inhibiting the Hedgehog pathway, effectively resensitized cancer cells to kinase inhibitor therapy. Treating erlotinib-resistant cancer cells with a fibroblast growth factor receptor (FGFR) inhibitor signficantly reduced the formation of cilia and also resensitized the cells to erlotinib therapy.

Exposure to drugs killed between 35% and 60% of formerly resistant cancer cells, which nearly doubled drug effectiveness. In lung cancer cells without cilia, for example, only 39% of cells survived treatment using erlotinib, compared with 72% of cells that still had cilia. The team suggests their findings indicate that “inhibition of cilia regulators such as FGFR may represent a good therapeutic strategy to overcome drug resistance in a variety of contexts.”

In a final round of experiments, the researchers confirmed an association between de novo drug resistance and ciliogenesis and demonstrated that inhibiting ciliogenesis using a chemical FGFR inhibitor led to increased cell death on exposure to the kinase inhibitor trametinib. In contrast, boosting cilia lengthening by knocking down Kif7 increased trametinib resistance. On the back of these results, the authors suggest that, similar to the models of acquired kinase inhibitor resistance, changes in ciliogenesis also appear to mediate de novo adaptive resistance to drug therapy.

“These data support a model wherein inhibition of certain kinases leads to increased activation of  FGFR (or other cilia promoting pathways), leading to enhanced ciliogenesis and concomitant Hedgehog pathway activation, thus facilitating the generation of inhibitor insensitive survival  signals,” they write. “Our study shows that aberrant ciliogenesis could serve as a functional platform for a variety of cancer drug resistance mechanisms (both de novo and acquired) and provides rationale for a broad therapeutic strategy to overcome resistance in a variety of settings.”

“Next, we aim to explore changes to cilia in more depth, to build a more detailed picture of how they are linked to cancer drug resistance and how they might be targeted to restore sensitivity to treatment,” Dr. Tanos states. “The research could open the door to new approaches for attacking cancers, which might block their escape routes from existing treatments,” adds Paul Workman, Ph.D., chief executive of the ICR.

Reference

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بارگذاری بیشتر در medical biotechnology

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