A team at the Institute of Cancer Research in London led by Dr. Barbara Tanos has found out that cellular organelles known as “cilia” may be a viable target for undermining many cancers’ drug resistance [1].

Study summary Primary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired and de novo resistance to a variety of kinase inhibitors, and found that, in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in ciliation seem to be linked to differences in the molecular composition of cilia and result in enhanced Hedgehog pathway activation. Notably, manipulating cilia length via Kif7 knockdown is sufficient to confer drug resistance in drug-sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. Our work establishes a role for ciliogenesis and cilia length in promoting cancer drug resistance and has significant translational implications.

What are cilia?

Cilia are tubular organelles found on the surfaces of eukaryotic cells, which have membrane-bound nuclei and make up multicellular organisms. Cilia can be thought of as a sort of “eyelashes”—indeed, that’s what their name means in Latin—with motor or sensory functions. Sensory cilia allow cells to receive chemical, thermal, and mechanical signals from the surrounding environment and trigger an appropriate response. Understandably, cilia are a critical component of our bodies, and their malfunction is behind a wide range of pathologies.

Size matters

The edge that has permitted cancer to largely elude our eradication efforts is evolutionary in nature. We can use a drug that exploits a certain vulnerability of its cells, but as cancer cells reproduce endlessly at a furious pace, some will have a mutation that makes them invulnerable to that specific drug. As more and more drug-resistant cells are created, they take over the vulnerable ones, making the cancer immune to that specific treatment.







The authors of this new research, which was published on June 5 in the online journal Cell Reports, wanted to investigate the role, until now rather unclear, that cilia play in cancer drug resistance. As they explained in the study’s introduction, cilia appear to inhibit or accelerate tumor growth even in the same tumor type, depending on the context; however, in their study, the scientists found out that cancers that became resistant to certain drugs had cells with either longer or more numerous cilia that displayed altered structural features.

Following this observation, the researchers proceeded to block ciliar growth in the drug-resistant cancer cells, finally exposing them to the drugs that they had developed resistance against. Interestingly, lack of cilia made the cancer vulnerable to the treatments again, enabling the drugs to wipe off up to 60% of the once-invulnerable cancer cells. Only 39% of lung cancer cells deprived of cilia managed to survive treatment with the drug erlotinib, while 72% of cancer cells with cilia survived it. Conversely, lengthening the cilia increased drug resistance, making previously vulnerable cancer cells immune to the treatment. Drug sensitivity in cancer cells was also restored by blocking certain signalling molecules within the cilia.

The way forward

The researchers think that cilia might play an important role in many cancers’ ability to evolve a resistance to a variety of drugs, and they might therefore be a good target for future therapeutic endeavors and perhaps even a universal way to get cancer to lower its shields. Next, the researchers plan to run further studies to deepen their understanding of how exactly cilia help confer cancer cells resistance to existing drugs and how to best target them to make cancers vulnerable again.

Literature







[1] Jenks, A. D., Vyse, S., Wong, J. P., Kostaras, E., Keller, D., Burgoyne, T., … & Cinatl, J. (2018). Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer. Cell reports, 23(10), 3042-3055.