Src Family Kinase Activity Is Up-Regulated in Hormone-Refractory Prostate Cancer

Abstract

Purpose: Although Src family kinase (SFK) inhibitors are now in clinical trials for the treatment of androgen-independent prostate cancer (AIPC), there are no studies relating SFK activation to patient survival. This study was designed to determine if SFK activation was up-regulated with the development of AIPC and if patients could be selected who were more likely to respond to therapy. Experimental Design: A unique cohort of matched prostate tumor samples, taken before hormone deprivation therapy and following hormone relapse, was used to determine by immunohistochemistry on an individual patient basis if SFK activity changed with progression to AIPC and whether this related to patient outcome measures. Using matched, hormone-sensitive and hormone-refractory cell lines, we determined if hormone status affected the way prostate cancer cells respond to suppression of SFK activity by the small-molecule inhibitor dasatinib.Results: In the current study, 28% of patients with AIPC exhibited an increase in SFK activity in prostate cancer tissue, these patients had significantly shorter overall survival (P < 0.0001), and activated SFK expression correlated with the presence of distant metastases. Dasatinib inhibited phosphorylation of Src and Lyn and the downstream substrate FAK in hormone-sensitive and hormone-refractory cell lines. Although migration was reduced by dasatinib in both cell lines, proliferation of hormone-refractory cells only was inhibited. Conclusion: Appropriate patient selection may allow better targeting of prostate cancer patients who are likely to respond to the treatment with SFK inhibitors at the same time improving the outcome of clinical trials.Prostate cancer is the most common cancer in men and is the second leading cause of cancer-related deaths in men in the United States and United Kingdom (1). Treatment options for locally advanced and metastatic prostate cancer are limited to androgen deprivation therapy or surgical castration. Unfortunately, nearly all of these patients eventually develop androgenindependent prostate cancer (AIPC) for which currently there are no established effective therapies.Our understanding of the mechanisms involved in the development of AIPC has considerably improved over the last decade. When deprived of androgen stimulation, androgensensitive prostate cancer (ASPC) cells develop the ability to survive and thrive by up-regulating oncogenic pathways where tyrosine kinases often play a crucial role (2). The nonreceptor tyrosine kinase Src is thought to facilitate the interaction between intracellular molecular cascades as well as form complexes with the androgen receptor (AR), which is expressed by the majority of AIPC cells. Tyrosine phosphorylation is an important factor in the regulation of AR activity resulting in translocation of the receptor into the nucleus and increase in DNA synthesis. Src activation by growth factors in prostate cancer cells has been shown to correlate with AR tyrosine phosphorylation, especially under androgen-depleted condi...

Oncogene-specific activation of tyrosine kinase networks during prostate cancer progression

“…This relationship results in robust activation of SRC tyrosine kinase and MAPK signaling (18). SRC activity was also observed in a subset of castration-resistant prostate cancer (CRPC) patients, which correlated with lower overall survival and increased metastatic disease (19). These data support the idea that tyrosine kinase activity may play a prominent role in prostate cancer progression in the absence of activating mutations.…”

Antitumor activity of 7RH, a discoidin domain receptor 1 inhibitor, alone or in combination with dasatinib exhibits antitumor effects in nasopharyngeal carcinoma cells

“…Furthermore, SRC is involved in the signal transduction mediated by HER kinases (40). In prostate cancer, SRC family kinases and FAK signaling are frequently hyperfunctional and have been associated with poor patient outcome, as well as resistance to antihormonal therapies (41). In addition, previous studies have demonstrated that SRC is involved in resistance to epidermal growth factor receptor inhibitors, which has been associated with poor outcomes in NPC patients treated with lapatinib and cetuximab (42,43).…”

Cancer-targeted therapies and radiopharmaceuticals

“…28 In breast cancer, Src kinases are higher expressed in malignant tissue compared with benign breast samples, 29 and in prostate samples increased Src expression correlates with a shorter time to castration response and poorer survival. 30 Dasatinib, an Src kinase inhibitor, prevented prostate cancer growth in a xenograft model in castrated mice. 31 Moreover, a number of clinical trials have assessed the potential of dasatinib in prostate cancer.…”