Inhibition of Src family kinases and receptor tyrosine kinases by dasatinib: possible combinations in solid tumors
Cet article passe en revue les travaux récents sur l'usage du dasatinib, un inhibiteur de multiples tyrosines kinases, en combinaison avec une hormonothérapie ou une chimiothérapie dans les tumeurs solides
Dasatinib is a small molecule tyrosine kinase inhibitor that targets a wide variety of tyrosine kinases implicated in the pathophysiology of several neoplasias. Among the most sensitive dasatinib targets are ABL, the SRC family kinases (SRC, LCK, HCK, FYN, YES, FGR, BLK, LYN, and FRK), and the receptor tyrosine kinases c-KIT, PDGFRalpha and beta, DDR1, c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration or invasion, and triggers apoptosis of tumoral cells. As a consequence, dasatinib reduces tumoral mass and decreases the metastatic dissemination of tumoral cells. Dasatinib also acts on the tumoral microenvironment. This is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favours osteogenesis, exerting a bone protecting effect. Several preclinical studies have shown that dasatinib potentiates the antitumoral action of various drugs used in the oncology clinic, paving the way for the initiation of clinical trials of dasatinib in combination with standard of care treatments for the therapy of various neoplasias. Trials using combinations of dasatinib with ErbB/HER receptor antagonists are being explored in breast, head and neck, and colorectal cancers. In hormone receptor positive breast cancer, trials using combinations of dasatinib with antihormonal therapies are ongoing. Dasatinib combinations with chemotherapeutic agents are also under development in prostate cancer (dasatinib plus docetaxel), melanoma (dasatinib plus dacarbazine) or colorectal cancer (dasatinib plus oxaliplatin plus capecitabine). Here we review the preclinical evidence that supports the use of dasatinib in combination for the treatment of solid tumors, and describe various clinical trials developed following a preclinical rationale.