Exploiting acquired vulnerabilities in fatty acid metabolism to overcome therapy resistance in castration resistant prostate cancer

Castration resistant prostate cancer (crPCA) remains refractory to
androgen deprivation therapy (ADT) and is invariably lethal. Therefore,
strategies in extending therapy response or overcoming therapy
resistance are sorely needed. Based on solid evidence that androgen
signalling drives fatty acid synthesis, rendering membrane lipids more
saturated and contributing to therapy resistance, we propose to exploit
fatty acid metabolism to (re)sensitise PCA cells to therapy. Specifically,
we postulate that androgen pathway inhibition (API), especially in
combination with fatty acid synthesis inhibitors confers a new vulnerability in
prostate cancer cells to compounds that elevate reactive oxygen species
(ROS). Moreover, by interfering with a novel mechanism in which cancer
cells can diminish their vulnerability to ROS by specifically sequestering
deleterious poly-unsaturated fatty acids (PUFA) into triacylglycerides
(TAGs), we propose a novel ADT/API sensitisation strategy with farreaching
consequences in PCA therapy