Molecular drivers of metastatic castrate-resistant prostate cancer: New roads to resistance

Numerous growth-inducing signaling pathways have been implicated in the development of metastatic castrate-resistant prostate cancer, but their cross-talk with androgen receptor functions remains poorly understood. A recent study published in Science Signaling by Chen et al.¹ has identified a novel androgen-mediated signaling axis driven by loss of SPDEF and gain of TGFBI to facilitate metastasis, which may explain the acquisition of resistance to androgen deprivation therapy. These findings suggest that therapeutic inhibition of androgen signaling may inadvertently promote castrate resistance by inhibiting tumor suppressive functions of the androgen receptor.