Other mechanisms responsible for Enz-resistant CRPC
RNA sequencing has shown that the NOTCH signalling pathways were associated with Enz resistance, which was independent of AR pathways. Notably, NOTCH1 signalling was activated in Enz-resistant cells, and inhibition of this pathway restored Enz function in vitro and in vivo (Farah, Li et al., 2019). In another short hairpin RNA (shRNA) screen of the bone-homing C4-2B CRPC cell line, several genes were found to be involved in the response to Enz. Three candidate genes, acetyl-CoA acetyltransferase 1 (ACAT1), mixed-lineage kinase 3 (MLK3), and PSMD12, which encodes the proteasome 26S subunit, were validated as supporters of Enz resistance in vitro. Further studies need to be conducted to verify the drivers of these genes and the level of in vivo resistance the confer (Kohrt, Awadallah et al., 2020). Moreover, an online database search and bioinformatics analysis showed that bone morphogenetic protein (BMP)-6/SMAD signalling was activated in Enz-resistant LNCaP cells. Further study indicated the role of phospholipase C (PLC)ε in regulating this pathway. Targeting the PLCε/BMP-6/SMAD pathway may be an alternative tactic to increase cell sensitivity to Enz (Yuan, Gao et al., 2019).
A key enzyme in cholesterol synthesis, 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR), has been found to be upregulated in Enz-resistant PCa cells. Aberrant HMGCR expression mediated Enz resistance of CRPC cells. Simvastatin alone or in combination with Enz in vitro and in vivo can inhibit the proliferation of Enz-resistant PCa cells via the suppression of the mTOR pathway, resulting in AR or AR-V degradation. Furthermore, cancer-associated fibroblasts (CAFs) induced a remarkable upregulation of cholesterol and steroid biosynthesis pathways in PCa cells. In addition, AKR1C3 and 3-hydroxy-methylglutaryl CoA synthase 2 (HMGCS2) were found to be significantly upregulated in PCa cells upon coculture with CAFs. The combination of simvastatin and AKR1C3 inhibitors showed the strongest growth inhibition, suggesting that the dual inhibition of cholesterol and steroid biosynthesis may be a promising method to overcome AR targeted therapy resistance (Kong, Cheng et al., 2018 , Neuwirt, Bouchal et al., 2020).