Table 2.

SOME CUSTOMIZED PHARMACOGENOMIC WAYS AGAINST INDIVIDUAL PCA RESISTANCE TO VARIOUS THERAPIES (mod. from Alberti C. G Chir. 2015;36:133–136).

Aberrant gene-due resistance to therapy	Personalized sensitizers to therapy
Cancer cell growth pathway hyperactivation:
- Overexpression of HER2 (Human epidermal growth factor receptor type 2 of tyrosine kinase).	- Trastuzumab (Herceptin) that, by blocking HER2, inhibits PCa cell proliferation.
- Phosphatidyl inositol 3-kinase(PI3K)-Akt/mammalian target of rapamicin (mTOR) pathway.	- NVP-BEZ 235 or NU7 441, as dual ATP-competitive PI3K and mTOR blockers. Zotarolimus, as analog of rapamicin, blocks mTOR.
- Janus tyrosine kinase - Signal transducer activator of transcription (Jak-STAT) pathway.	- AG 490, as a suitable specific blocker of Jak-STAT pathway, can sensitize the PCa cells to therapy. Ruxolitinib and fludarabine are respectively selective inhibitors of Jak 1/2 and STAT3.
- Interactions between overexpressed MDM2 (mouse double minute 2) and p53 with subsequent lack of p53 normal function, whence enhancement of cancer cell growth.	- Nutlins, as cis-imidazoline analogs, to prevent p53-MDM2 interactions, so inhibiting cancer cells growth meanwhile restoring PCa therapy-sensitivity. MDM2 antagonist Nutlin-3 also facilitates apoptosis.
Cancer cell apoptotic pathway evasion:
- Suppression of apoptosis machinery by overexpression of antiapoptotic Bcl-2 gene.	- HA14-1 and ABT-263 (Navitoclax), as inhibitors of Bcl-2, facilitate the apoptotic process.
- Suppression of proteolytic cleavage of poly(ADP-ribose) polymerase-1 (PARP-1), so preventing apoptosis-proper DNA fragmentation.	- Olaparib, veliparib, niraparib, as blockers of PARP-1, allow the cancer cell death, so it reaching the prostate cancer cell therapy sensitization.
- Survivin gene overexpression, by interfering with caspase activity, supports cancer cell survival.	- YM155, as survivin inhibitor, can restore sensitivity of prostate cancer cells to therapy.
- Clusterin, as inhibitor of Bax proapoptotic activity, protects cancer cells from TGFβ-induced apoptotic mechanisms.	- OGX-011 antisense nucleotide, by promoting a down regulation of clusterin expression, can restore cancer cell apoptosis and therapy-sensitivity.
Cancer stem cell-related therapy-resistance:
- Particular gene mutation-dependent over-activation of stem cell specific pathways – such Wnt/βcatenin-, Hedgehog-and Notch signaling pathways – plays an important role in inducing both self-renewal process and PCa therapy resistance.	- Perifosine, besides blocking the Akt pathway, can also inhibit the Wnt signaling, with following restoration of tumor therapy-sensitivity.
- CXCR4 (chemochine CXC of receptor 4), by interacting with its ligand CXCL12, can cause both cancer stem cell chemo- and radioresistance.	- Foreseeable block of CXCR4-CXCL12 interactions should represent a promising opportunity to refine the prostate cancer sensitivity to such therapies.
- Also PSCA (prostate stem cell antigen) gene overexpression can promote, because of vimentin/β-catenin increase compared with E-cadherin decrease, prostate carcinogenesis with further PCa progression and resistance to therapies.	- PSCA knock-down decreases PCa progression and metastatic potentials meanwhile restoring the PCa cells sensitivity to therapies.