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).