Indeed a recent study , performed in a small series of CRPCa bone metastases (n = 30), demonstrated that expression of AR variants lacking the ligand binding domain was associated with poor prognosis and shorter survival rates.
As mentioned above, intraprostatic androgen synthesis may support PCa cell growth even in the virtual absence of androgens contributing to development of CRPCa .
Alternative splicing events occur in approximately 90% of human genes and such events are evident in PCa [27, 43] where, in fact, it is an important mechanism of PCa resistance to AR-targeted therapy and further progression to CRPCa. Recent studies have identified several AR splice variants, and, despite having slightly different structures, a common characteristic is the absence of the LBD and the AF-2 domain in these isoforms .
On the other hand, the deregulated PI3K/AKT pathway during PCa progression appears to be a reason for the resistance against some anticancer drugs; an example is the resistance to sunitinib in CRPCa, which is correlated with the loss of PTEN expression 122].
PCa cells have upregulated expression of both IL-6 and its receptor IL-6R , as well as elevated circulating levels of IL-6 in patients with metastatic PCa and CRPCa [159-161], correlating IL-6 production to cancer morbidity [162-164] and differential autocrine and paracrine modulation of PCa cell lines [141,164-166].
The expression of Ras or its effector-loop mutants reduces the androgen-dependent requirement of LNCaP cells for growth and increases their PSA expression and tumorigenicity, whereas dominant negative N17-Ras can restore androgen sensitivity to the CRPCa C4-2 cell line [22,199].