SCD1 Inhibition May Strengthen Enzalutamide Against Resistant Prostate Cancer

SCD1 is an enzyme that helps prostate-cancer cells convert saturated fatty acids into monounsaturated fatty acids, which support cell membranes, energy storage and survival signaling. Functional research suggests that some tumors rely on SCD1 activity. Blocking this pathway can disrupt lipid synthesis, androgen-receptor signaling and survival pathways such as AKT.

This provides the rationale for combining an SCD1 inhibitor with enzalutamide. Enzalutamide blocks the androgen receptor, but cancer cells can adapt by changing their lipid metabolism and increasing their dependence on fatty-acid desaturation. Inhibiting SCD1 at the same time may remove this metabolic escape route: enzalutamide suppresses the hormonal growth signal, while SCD1 inhibition deprives the cell of lipids needed to maintain membranes and survival mechanisms. Earlier preclinical research found that this combination reduced prostate-cancer cell proliferation more effectively than either treatment alone and could delay enzalutamide resistance.

Aramchol, an SCD1 inhibitor already being tested in a phase 3 trial for NASH, combined with enzalutamide produced a 3–4-fold increase in cell death compared with enzalutamide alone in patient derived VCaP cells. This model expresses the androgen receptor, AR-V7 and the TMPRSS2-ERG fusion, features associated with advanced and treatment-resistant prostate cancer. The result is therefore biologically interesting, but it remains an early in-vitro finding.  At this stage, the combination is a promising strategy for attacking both androgen signaling and the lipid metabolism that may help tumors escape it.

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