Targeted inhibition of SRC kinase with dasatinib blocks thyroid cancer growth and metastasis
Clinical Cancer Research, 06/12/2012
Chan CM et al. – Src is a central mediator of thyroid cancer growth and metastasis, indicating that Src inhibitors may have a higher therapeutic efficacy in thyroid cancer, as both antitumor and antimetastatic agents.Methods
- The effects of dasatinib on thyroid cancer growth, signaling, cell cycle, and apoptosis were evaluated in vitro.
- The therapeutic efficacy of dasatinib was further tested in vivo using an orthotopic and a novel experimental metastasis model.
- Expression and activation of SFKs in thyroid cancer cells was characterized, and selectivity of dasatinib was determined using an Src gatekeeper mutant.
- Dasatinib treatment inhibited Src signaling, decreased growth, and induced cell-cycle arrest and apoptosis in a subset of thyroid cancer cells.
- Immunoblotting showed that c-Src and Lyn are expressed in thyroid cancer cells and that c-Src is the predominant SFK activated.
- Treatment with dasatinib blocked PTC tumor growth in an orthotopic model by more than 90% (P = 0.0014).
- Adjuvant and posttreatment approaches with dasatinib significantly inhibited metastasis (P = 0.016 and P = 0.004, respectively).