Disparate anticancer activity of structurally similar multi-kinase inhibitors through cumulative differential effects on individual targets

ABSTRACT: Despite recent improvements many cancer patients do not respond to immune or targeted drugs and require new therapies. Through a systems pharmacology approach including phenotypic screening, chemical and phosphoproteomics and RNA-Seq, we elucidated the mechanism of action underlying the differential anticancer activity of two structurally related multi-kinase inhibitors, foretinib and cabozantinib, in lung cancer cells. Biochemical and cellular target validation using probe molecules and RNA interference revealed a polypharmacology mechanism of foretinib involving MEK1/2, FER and AURKB, which were each more potently inhibited by foretinib than cabozantinib. Based on this, we rationally developed a synergistic combination of foretinib with barasertib, a more potent AURKB inhibitor, for MYC-amplified small cell lung cancer. This systems pharmacology approach showed that small structural changes of drugs can cumulatively through multiple targets result in pronounced anticancer activity differences and that detailed mechanistic understanding can lead to new repurposing opportunities for cancers with unmet medical need.

ORGANISM(S): Homo sapiens

PROVIDER: GSE126850 | GEO | 2019/06/25

REPOSITORIES: GEO