BioCentury
ARTICLE | Distillery Therapeutics

Therapeutics: Discoidin domain receptor tyrosine kinase 1 (DDR1); Notch pathway; K-Ras (KRAS)

February 18, 2016 8:00 AM UTC

Patient sample and mouse studies suggest combining inhibitors of DDR1 and the Notch pathway could help treat KRAS-mutant lung cancer. In 554 tumor samples from patients with lung adenocarcinoma, the presence of mutant KRAS was associated with high DDR1 levels and high Notch pathway activity. In a transgenic mouse model of human KRAS-mutant lung cancer, two tool compounds that inhibit DDR1 and Notch pathway activity, respectively, decreased tumor growth compared with the generic chemotherapies cisplatin plus paclitaxel or either tool compound alone. In patient-derived xenograft mouse models of KRAS-mutant lung adenocarcinoma, Sprycel dasatinib, which inhibits the Src-DDR1 interaction, plus demcizumab, which inhibits the Notch ligand δ-like 4 (DLL4), decreased tumor growth compared with cisplatin plus paclitaxel. Next steps could include testing DDR1 and Notch pathway inhibitors in other KRAS-mutant cancers.

Bristol-Myers Squibb Co. and Otsuka Pharmaceutical Co. Ltd market Sprycel, a small kinase inhibitor of BCR-ABL and Src kinases, to treat acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) and have the compound in Phase II testing to treat breast and pancreatic cancers and Phase I testing to treat leukemia. ...