A Cell Reports study from Institute of Cancer Research (ICR) researchers and colleagues identified cilia on tumor cells as a new, potentially universal target for sensitizing drug-resistant cells to kinase inhibitors. The research suggests inhibiting fibroblast growth factor receptor (FGFR) -- which regulates cilia length -- or other cilia-promoting pathways could improve the efficacy of kinase inhibitors.
Primary cilia are sensory organelles that sit on the cell surface and detect chemical stimuli. Research suggests these organelles might play an important role in cancer cell survival for some tumor types, and several oncogenes, including the kinase EGFR and KRAS (K-Ras), reside in the organelles.
The ICR researchers found that drug-resistant human cancer cell lines had distinct differences in cilia quantity and length compared with drug-sensitive cells. They saw more, longer cilia in three cell lines with acquired resistance to kinase inhibitors -- EML4-ALK oncogenic fusion protein (EML4-ALK)-positive lung cancer resistant to an anaplastic lymphoma kinase (ALK) inhibitor, an EGFR-mutant non-small cell lung cancer (NSCLC) resistant to EGFR inhibitor Tarceva erlotinib, and a rhabdomyosarcoma cell line resistant to Sprycel dasatinib, which inhibits BCR-ABL tyrosine kinase (BCR-ABL) and Src.
The team observed greater numbers and longer lengths of the antenna-like structures in a KRAS-mutant human lung carcinoma cell line refractory to MAP kinase kinase 1 (MAP2K1; MEK1) and MAP2K2 inhibitor Mekinist trametinib, suggesting ciliogenesis is up-regulated during de novo drug resistance as well as acquired resistance.
Across the drug-resistant cancer cell lines, siRNA knockdown of intraflagellar transport 88 homolog (IFT88; TG737) or sodium channel and clathrin linker 1 (SCLT1) -- both of which contribute to the formation of primary cilia -- decreased cell growth in the presence of the appropriate resisted kinase inhibitor, compared with control siRNA.
Additionally, treating the cancer cell lines with a tool compound FGFR inhibitor plus the respective kinase inhibitor diminished cell growth.
The researchers also identified longer cilia lengths or greater numbers of cilia in chemotherapy-resistant KRAS-mutant lung cancer cells, suggesting the organelles might contribute to resistance against other therapeutic agents.