BACKGROUND: Despite its initial positive response to hormone ablation therapy, 
prostate cancers invariably recur in more aggressive, treatment resistant forms. 
The lack of our understanding of underlying genetic alterations for the 
transition from androgen-dependent (AD) to ADI prostate cancer growth hampers 
our ability to develop target-driven therapeutic strategies for the efficient 
treatment of ADI prostate cancer.
METHODOLOGY/PRINCIPAL FINDINGS: By screening a library of activated human 
kinases, we have identified TPL2, encoding a serine/threonine kinase, as driving 
ADI prostate cancer growth. TPL2 activation by over-expressing either wild-type 
or a constitutively activated form of TPL2 induced ADI growth, whereas the 
suppression of TPL2 expression and its kinase activity in ADI prostate cancer 
cells inhibited cell proliferation under androgen-depleted conditions. Most 
importantly, TPL2 is upregulated in ADI prostate cancers of both the Pten 
deletion mouse model and the clinical prostate cancer specimens.
CONCLUSIONS/SIGNIFICANCE: Together these data suggest that TPL2 kinase plays a 
critical role in the promotion of ADI prostate cancer progression. Furthermore, 
the suppression of TPL2 diminishes ADI prostate cancer growth and a high 
frequency of TPL2 overexpression in human ADI prostate cancer samples validates 
TPL2 as a target for the treatment of this deadly disease.