Modulation of de Novo Lipogenesis Improves Response to Enzalutamide Treatment in Prostate Cancer

SIMPLE SUMMARY: Prostate cancer cells produce lipids via the activation of a specific pathway called fatty acid synthesis, also known as De novo lipogenesis. This pathway is essential for the survival and growth of most types of cancer cells, including prostate cancer. In our study, we showed that prostate cancer cells activate this lipid synthesis pathway to become more aggressive and develop resistance to commonly used therapeutic agents for advanced prostate cancer such as enzalutamide, an effective and commonly used androgen receptor (AR) targeted agent. Interestingly, by combining enzalutamide with a lipid synthesis pathway inhibitor, we were able to show that growth of prostate cancer tumors was more effectively reduced than with either agent alone. We also showed that this combination led to cell stress and death by changing the lipid content in the cell. These important findings could lead to new therapeutic strategies combining effective AR targeted therapies with lipid synthesis inhibitors for the treatment of advanced prostate cancer. ABSTRACT: De novo lipogenesis (DNL) is now considered as a hallmark of cancer. The overexpression of key enzymes of DNL is characteristic of both primary and advanced disease and may play an important role in resistance to therapies. Here, we showed that DNL is highly enhanced in castrate resistant prostate cancer (CRPC) cells compared to hormone sensitive and enzalutamide resistant cells. This observation suggests that this pathway plays an important role in the initiation of aggressive prostate cancer and in the development of enzalutamide resistance. Importantly, here we show that both prostate cancer cells sensitive and resistant to enzalutamide are dependent on DNL to proliferate. We next combined enzalutamide with an inhibitor of Stearoyl CoA Desaturase 1 (SCD1), an important enzyme in DNL, and observed significantly reduced tumor growth caused by the important change in tumoral lipid desaturation. Our findings suggest that the equilibrium between monounsaturated fatty acids and saturated fatty acids is essential in the establishment of the more aggressive prostate cancer phenotype and that the combination therapy induces a disruption of this equilibrium leading to an important decrease of cell proliferation. These findings provide new insights into the role of DNL in the progression of prostate cancer cells. The study also provides the rationale for the use of an inhibitor of SCD1 in combination with enzalutamide to improve response, delay enzalutamide resistance and improve disease free progression.