IL-17RD or inhibition of ZEB1 to sensitize lung cancer to MEK inhibition

INDICATION: Lung cancer

Patient sample, cell culture and mouse studies suggest IL-17RD or blocking ZEB1 via miR-200 expression or HDAC inhibition could sensitize lung cancer to MEK inhibitors. In tumor samples from lung cancer patients, high levels of ZEB1 protein were associated with low levels of MEK signaling. In human and mouse lung cancer cell lines, overexpression of IL-17RD, which is transcriptionally repressed by ZEB1, increased sensitivity to the MEK1/MEK2 inhibitor selumetinib compared with normal IL-17RD expression. In a mouse model of lung cancer treated with selumetinib, co-treatment with a synthetic mimic of miR-200 -- which represses ZEB1 expression -- the HDAC1/HDAC2 inhibitor mocetinostat or IL-17RD encoded in a lentiviral vector decreased tumor growth compared with a non-specific miRNA mimic, vehicle or empty vector, respectively. Next steps could include testing the combination therapies in patient-derived xenograft (PDX) mouse models of lung cancer...