The role of SRC family kinases in the development and progression of prostate cancer.
MD thesis, University of Glasgow.
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Prostate cancer is the most common cancer in men and the second leading cause of cancer-related death in western world. Typically, the treatment of advanced and metastatic prostate cancer consists of castration therapy, which suppresses the development of the disease for 2 years in average. Virtually all patients, undergoing androgen deprivation therapy eventually develop castration-resistant prostate cancer. Currently, only taxane class of drugs has been proven to provide short survival advantage in patients with castration-resistant prostate cancer. This form of the disease is the cause of significant morbidity, resulting in long periods of gradual deterioration of patients’ condition, pain related to local extension of the tumour and distant metastases, renal failure due to the invasion into the ureters etc.
Castration resistance allows prostate tumours to progress despite androgen deprivation. Several mechanisms have been described, outlining the nature of molecular pathways, employed by prostate cancer cells in order to proliferate and migrate in low androgen environment. Hormone-sensitive prostate cancer cells rely on androgens for their growth needs with androgens acting through the androgen receptor (AR). In castration-resistant prostate cancer AR can be activated by reduced concentrations of androgens, AR antagonists, protein kinases or bypassed altogether. Detailed knowledge of these processes should allow better understanding of molecular patterns, driving the progression of prostate cancer and, ultimately, could lead to the development of novel molecular targeted therapies.
Molecular pathways, implicated in the development of castration-resistant prostate cancer frequently show cross-talk, resulting in the ability of cancer cells to adapt to changing microenvironment. Inhibiting the proteins, facilitating these cross-talks provides an attractive targeting mechanism. Src family of non-receptor tyrosine kinases (SFK) represent proteins involved in the development of various solid malignancies, including prostate cancer. These proteins are often found on the cross-roads of intracellular pathways, integrating molecular systems into complex signalling networks. SFK interact with receptor tyrosine kinases, G-protein coupled receptors, motility and adhesion factors and, thus, influence multiple cell functions. In prostate cancer, SFK have been demonstrated to form complexes with AR, activating AR by means of tyrosine phosphorylation.
SFK inhibitory compounds have been developed and are now in Phase II clinical trial in patients with castration-resistant prostate cancer. However, there is considerable lack of data regarding the role of SFK expression and activation in prostate cancer in clinical settings. In this thesis, we studied the role of SFK in prostate cancer using matched paired prostate cancer samples, taken from patients prior to castration therapy being administered and following the development of castration resistance. Using paired tissue specimens allows following molecular changes through the natural history of the disease and correlating these changes with various clinical parameters. We also conducted in vitro experiments, employing hormone-sensitive LNCaP cell line and its counterpart, castration-resistant LNCaP-SDM cell line, developed by gradual withdrawal of androgens from the culture medium.
Our main finding is that in a subgroup of prostate cancer patients, the increase in SFK activity in the transition of prostate cancer from hormone-sensitive to castration-resistant state is associated with significant decrease in survival (p<0.0001). Furthermore, the presence of bone metastases in patients with castration-resistant prostate cancer was associated with higher SFK activity in prostate tissue specimens. Our in vitro experiments have demonstrated that in prostate cancer the relationship between SFK and AR are important as androgen deprivation resulted in significant reduction in SFK activity. Using SFK inhibitor dasatinib, we have shown that in prostate cancer cell lines, SFK activity was inhibited at low nanomolar concentrations. Inhibition of SFK activity was accompanied by the inhibition of downstream protein FAK at Src-specific phsophorylation site. Although the treatment with SFK inhibitor suppressed migration of both LNCaP and LNCaP-SDM cell lines, only proliferation of LNCaP-SDM cell was affected by dasatinib.
Taken together, our date suggests that SFK inhibitors may have a role in the treatment of castration-resistant prostate cancer. However, important considerations should be given to the molecular heterogeneity of prostate cancer in order to improve the outcomes of clinical trials and the response to treatment. There is considerable evidence that SFK inhibitors suppress prostate cancer cells migration and future studies will hopefully further clarify their role in cancer cells proliferation.
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