ACK1 Activation in Prostate Cancer
Resistance to Androgen deprivation therapies (ADT) is closely associated with abnormal tyrosine kinase signaling. Non-receptor tyrosine kinases (NRTKs) such as ACK1 interacts with AR in an androgen-independent manner. Importantly, CRPCs exhibited significant ACK1 overexpression. Further, LNCaP cells that are poorly tumorigenic in castrated mice formed robust CRPC tumors following expression of activated ACK1. Significantly, the expression of activated ACK1 correlates positively with the progression of disease to CRPC stage, and PC patients whose tumors display moderate to strong staining of activated ACK1 have poor prognosis. Figure on right shows:
(A) TMA sections representing different prostate cancer stages were stained with pTyr284-ACK1antibodies.
(B) Increasing expression of pTyr284-ACK1 in later stages of prostate cancer.
(C) Kaplan-Meier survival curves shows that individuals with prostate cancer that have moderate to strong staining of pTyr284-ACK1(>2 )have a significantly worse overall survival outcome than those with lower pTyr284-ACK1 levels.
ACK1 in Triple Negative Breast Cancer (TNBC)
Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are commonly classified as triple negative breast cancer (TNBC). These tumors are often aggressive and difficult to treat due to the lack of effective targeted therapy. We have uncovered that the non-receptor tyrosine kinase ACK1/TNK2 is activated in a majority of aggressive TNBC cell lines. Further, we show that high expression of ACK1 correlates with high proliferation, invasion and colony forming ability. We demonstrate that knockdown ACK1 expression can substantially suppress the invasiveness and proliferation advantage of TNBC cells in vitro.