Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer

Abstract

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 cilia length seem to be linked to the lack of recruitment of Kif7 and IFT81 to cilia tips, and result in enhanced hedgehog pathway activation. Notably, 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. The identification of a broad mechanism of pathway-unbiased drug resistance, represents a major advancement in oncology, and helps define a specific and important role for cilia in human cancer.