Dasatinib: A potent SRC inhibitor in clinical development for the treatment of solid tumors

Abstract

SRC is a tyrosine kinase that plays a role in oncogenic, invasive and bone-metastatic processes. It has therefore been prioritized as a candidate therapeutic target in patients with solid tumors. Several SRC inhibitors are now in development, of which dasatinib has been most explored. Preclinical studies in a wide variety of solid tumor cell lines, including prostate, breast and glioma, have shown that that dasatinib acts as a cytostatic agent, inhibiting the processes of cell proliferation, invasion and metastasis. Dasatinib also inhibits the activity of osteoclasts, which have a major role in the development of metastatic bone lesions. Dasatinib has additive or synergistic activity in combination with a number of other agents, including cytotoxic agents and targeted therapies, providing a rationale for combination treatment in a clinical setting. Emerging clinical data with dasatinib support experimental observations, with preliminary phase 1 and 2 data demonstrating activity, both as a single agent and as combination therapy, in a range of solid tumors. Future clinical trials will further assess the clinical value of SRC inhibition with dasatinib.

Involvement of EphA2-mediated tyrosine phosphorylation of Shp2 in Shp2-regulated activation of extracellular signal-regulated kinase

“…To further confirm the importance of tyrosine kinase activity, we examined the effect of Dasatinib, a potent inhibitor for EphA2, on the activation of Erk and on the phosphorylation of Shp2. 20 Treatment of the cells expressing Shp2T468M and EphA2 with Dasatinib resulted in a rapid decrease in Erk phosphorylation as well as in the phosphorylation of Shp2 and EphA2 (Figures 5b and c). We finally examined whether EphA2 directly phosphorylates Shp2 in vitro using purified EphA2 and Shp2.…”

Pulmonary Arterial Hypertension in Patients Treated by Dasatinib

“…5 In addition, dasatinib is currently being tested in other malignant disorders, such as melanoma and breast, head and neck, ovarian, and non-small-cell lung cancers. 9 Although TKIs are usually well tolerated, these agents are nonetheless characterized by systemic toxicity. Important side effects of imatinib include edema, musculoskeletal pains, diarrhea, nausea, rash, abdominal pain, fatigue, headache, leucopenia, neutropenia, thrombocytopenia, anemia, and elevated liver enzymes, as well.…”

Dasatinib plus Capecitabine for Advanced Breast Cancer: Safety and Efficacy in Phase I Study CA180004

“…Dasatinib, a potent orally available SFK inhibitor (22), is being studied in various solid tumors (23). Preclinical data suggest that dasatinib has therapeutic potential in breast cancer, including inhibition of "triple-negative" breast cancer cell lines in vitro (24,25), inhibition of breast cancer bone metastasis in in vivo models (9,26), and by other mechanisms (27,28).…”