Molecular Pharmacology of Dasatinib Provides Unique Insights into the Mechanistic Basis of Success and Failure of Targeted Cancer Therapy.

Abstract

Despite the enthusiasm for targeted cancer therapies in preclinical studies and the success of a select few drugs, many promising drug candidates fail in clinical trials. The gap between preclinical promise and clinical outcomes underscores the need to investigate factors influencing the success or failure of targeted therapies. Dasatinib, an inhibitor of Abl and Src protein tyrosine kinases, is highly effective toward chronic myeloid leukemia (CML) by targeting BCR-Abl, but it is ineffective against solid tumors when targeting Src kinases. A review reveals cytotoxic inhibition is a key attribute predictive of dasatinib's clinical efficacy toward CML, and cytostatic inhibition by targeting Src kinases is the underlying reason for the preclinical promise and clinical inefficacy toward solid tumors. The analysis reveals that preclinical cytotoxic inhibition is highly predictive of clinical efficacy and shows that cancer regression can only be achieved when the drug-target is an essential oncogenic driver in a monodriver cancer. The analysis highlights dasatinib's potential in achieving stable disease in solid tumors, supporting its use in combination therapies.