ACTIVITY OF A NOVEL LYN KINASE INHIBITOR IN TRIPLE NEGATIVE BREAST CANCER

Abstract

Src Family Kinases (SFKs) play pivotal roles in cell invasion, proliferation, and angiogenesis. Aberrant activation of the SFKs contributes to various oncogenic pathways in cancer. Interestingly, of the various breast cancer subtypes, the Triple Negative Breast Cancer (TNBC) is most sensitive to SFK inhibition. Stellar pre-clinical results thus propelled SFK inhibitors into many clinical trials. However, most trials ended with dismal results and it was retrospectively realised that SFK inhibitors sensitivity is not associated with the presumed Src activity. On the other hand, increasing evidences are alluding to other SFK members such as Lyn as a better target for SFK inhibitors over Src. Bioinformatics analyses reveal that Lyn expression level is indeed strongly correlated with the TNBC group and with the tumors enriched in EMT features. Therefore, in order to explore the feasibility of targeting Lyn for treatment of TNBC, an in-house series of SFK inhibitors were designed and synthesized. Within the series, CHL-4 has shown to be a promising candidate both at the in vitro and in vivo level.