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L cell lung cancer, respectively [249,250]. In prostate cancer, AXL was found to be overexpressed in docetaxel-resistant cell lines, and AXL overexpression alone was discovered enough to induce resistance to docetaxel [251]. The inhibition of AXL abated EMT phenotypic options and suppressed tumor proliferation and migration, positing AXL as a probable Mineralocorticoid Receptor review therapeutic target to overcome docetaxel resistance [251]. The PI3K/AKT survival signaling pathway has also been implicated in shaping the EMT phenotypic landscape inside the prostate tumor microenvironment. Chen and colleagues probed the PI3K/AKT pathway utilizing the tumor suppressor inositol polyphosphate 4-phosphatase B (INPP4B) on prostate cancer cells, obtaining that overexpression of INPP4B led to elevated sensitivity to docetaxel [252]. Mechanistically, INPP4B was found to inhibit the PI3K/AKT pathway, too as upregulate E-cadherin and lower levels of vimentin, fibronectin, and N-cadherin [252], thus the PI3K/AKT pathway may be a hyperlink between docetaxel resistance and EMT. Additionally, pre-clinical models have demonstrated that splice variants of AR, most notably AR-V7, are linked to EMT and mesenchymal phenotypes [253,254]. The EMT transcriptional suppressor SNAIL enables a prospective hyperlink among full-length AR, AR splice variants and EMT, as growing levels of SNAIL market antiandrogen resistance and increased AR activity, whereas the repression of SNAIL re-sensitized resistant prostate cancer cells to enzalutamide [255]. The anoikis-driven antitumor effect of 1-adrenoreceptor antagonists promises a safe-strategy in treating sophisticated disease–both therapeutically-resistant and castrationsensitive prostate cancer [143,256,257]. Quinazoline-based compounds developed just after the pharmacological optimization of 1-adrenoceptor antagonists trigger phenotypic reversion of EMT to MET and induce anoikis towards overcoming resistance to AR antiandrogens in pre-clinical models of sophisticated prostate cancer [143,25759]. 3. Conclusions Because the original operate by Charles Huggins in 1941 around the effects of ADT on progression to lethal disease, the emergence of castration resistance in sufferers with prostate cancer has reinforced the require for understanding actionable drivers of prostate cancer progression beyond AR, its ligands, and downstream targets. Prostate cancer is remarkably heterogenous and driven by a host of molecular things; evidence-based knowledge from the genomic and molecular underpinnings of PCa has paved the way for personalized remedies and reputable biomarkers with diagnostic or prognostic value. The PARP (poly (adenosine diphosphate (ADP)-ribose) polymerase) inhibitor olaparib and the lncRNAInt. J. Mol. Sci. 2021, 22,15 ofbiomarker PCA3 mentioned previously are two such examples. Olaparib, originally αLβ2 Source applied to treat BRCA-driven ovarian cancers [260], was not too long ago FDA approved last year for the remedy of mCRPC in men with alterations in genes involved in homologous recombination repair who failed antiandrogen therapy [70]. PARP is an enzyme involved in a number of DNA repair pathways and in repairing single strand breaks, which ultimately lead to cell death if not addressed [261]. Interestingly, and fittingly so, current mechanistic proof revealed that the silencing of PARP1 in prostate cancer cells suppresses their development and induces MET [262]. Non-coding RNAs are as wealthy and diverse in function as they may be in quantity, and intense efforts pursue their prospective to turn out to be clinical.