Inhibition of Src Family Kinases and Receptor Tyrosine Kinases by Dasatinib: Possible Combinations in Solid Tumors

• Published in: Clinical cancer research Vol. 17; no. 17; pp. 5546 - 5552
• Main Authors: MONTERO, Juan Carlos, SEOANE, Samuel, OCANA, Alberto, PANDIELLA, Atanasio
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01-09-2011
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Dasatinib; Humans; Medical sciences; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplasm Invasiveness; Neoplasm Metastasis - drug therapy; Neoplasms - drug therapy; Pharmacology. Drug treatments; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; src-Family Kinases - antagonists & inhibitors; Thiazoles - pharmacology; Thiazoles - therapeutic use; Tumor Microenvironment - drug effects; Tumors; Antineoplastic agent; Dasatinib; Solid tumor; Drug combination; Tyrosine kinase inhibitor; trk receptor; Multikinase inhibitor; Malignant tumor; Inhibition; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-10-2616

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, platelet-derived growth factor receptor (PDGFR) α and β, discoidin domain receptor 1 (DDR1), c-FMS, and ephrin receptors. Dasatinib inhibits cell duplication, migration, and invasion, and it 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, which is particularly important in the bone, where dasatinib inhibits osteoclastic activity and favors 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), and 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.