jnj-40346527 and Lung-Neoplasms

In the present work we show that multiple lung cancer cell lines contain cisplatin resistant cell subpopulations expressing the Colony-Stimulating-Factor-Receptor-1 (CSF-1R) and surviving chemotherapy-induced stress. By exploiting siRNA-mediated knock down in vitro and the use of an investigational CSF-1R TKI (JNJ-40346527) in vitro and in vivo, we show that expression and function of the receptor are required for the clonogenicity and chemoresistance of the cell lines. Thus, inhibition of the kinase activity of the receptor reduced the levels of EMT-associated genes, stem cell markers and chemoresistance genes. Additionally, the number of high aldehyde dehydrogenase (ALDH) expressing cells was reduced, consequent to the lack of cisplatin-induced increase of ALDH isoforms. This affected the collective chemoresistance of the treated cultures. Treatment of tumor bearing mice with JNJ-40346527, at pharmacologically relevant doses, produced strong chemo-sensitizing effects in vivo. These anticancer effects correlated with a reduced number of CSF-1Rpos cells, in tumors excised from the treated mice. Depletion of the CD45pos cells within the treated tumors did not, apparently, play a major role in mediating the therapeutic response to the TKI. Thus, lung cancer cells express a functional CSF-1 and CSF-1R duo which mediates pro-tumorigenic effects in vivo and in vitro and can be targeted in a therapeutically relevant way. These observations complement the already known role for the CSF-1R at mediating the pro-tumorigenic properties of tumor-infiltrating immune components.

Topics: Aldehyde Dehydrogenase; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzothiazoles; Carcinogenesis; Cell Line, Tumor; Cisplatin; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Gene Knockdown Techniques; Humans; Imidazoles; Leukocyte Common Antigens; Lung Neoplasms; Macrophage Colony-Stimulating Factor; Male; Mice; Mice, Inbred NOD; Mice, SCID; Phosphorylation; Picolinic Acids; Protein Kinase Inhibitors; Pyridines; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; RNA Interference; RNA, Small Interfering; Signal Transduction; Xenograft Model Antitumor Assays