Combined AKT and MEK Pathway Blockade in Pre-Clinical Models of Enzalutamide-Resistant Prostate Cancer
- PMID: 27046225
- PMCID: PMC4821639
- DOI: 10.1371/journal.pone.0152861
Combined AKT and MEK Pathway Blockade in Pre-Clinical Models of Enzalutamide-Resistant Prostate Cancer
Abstract
Despite recent improvements in patient outcomes using newer androgen receptor (AR) pathway inhibitors, treatment resistance in castrate resistant prostate cancer (CRPC) continues to remain a clinical problem. Co-targeting alternate resistance pathways are of significant interest to treat CRPC and delay the onset of resistance. Both the AKT and MEK signaling pathways become activated as prostate cancer develops resistance to AR-targeted therapies. This pre-clinical study explores co-targeting these pathways in AR-positive prostate cancer models. Using various in vitro models of prostate cancer disease states including androgen dependent (LNCaP), CRPC (V16D and 22RV1) and ENZ-resistant prostate cancer (MR49C and MR49F), we evaluate the relevance of targeting both AKT and MEK pathways. Our data reveal that AKT inhibition induces apoptosis and inhibits cell growth in PTEN null cell lines independently of their sensitivity to hormone therapy; however, AKT inhibition had no effect on the PTEN positive 22RV1 cell line. Interestingly, we found that MEK inhibition had greater effect on 22RV1 cells compared to LNCaP, V16D or ENZ-resistant cells MR49C and MR49F cells. In vitro, combination AKT and MEK blockade had evidence of synergy observed in some cell lines and assays, but this was not consistent across all results. In vivo, the combination of AKT and MEK inhibition resulted in more consistent tumor growth inhibition of MR49F xenografts and longer disease specific survival compared to AKT inhibitor monotherapy. As in our in vitro study, 22RV1 xenografts were more resistant to AKT inhibition while they were more sensitive to MEK inhibition. Our results suggest that targeting AKT and MEK in combination may be a valuable strategy in prostate cancer when both pathways are activated and further support the importance of characterizing the dominant oncogenic pathway in each patient's tumor in order to select optimal therapy.
Conflict of interest statement
Figures
Similar articles
-
Combination AZD5363 with Enzalutamide Significantly Delays Enzalutamide-resistant Prostate Cancer in Preclinical Models.Eur Urol. 2015 Jun;67(6):986-990. doi: 10.1016/j.eururo.2014.08.006. Epub 2014 Aug 20. Eur Urol. 2015. PMID: 25151012
-
Reciprocal feedback inhibition of the androgen receptor and PI3K as a novel therapy for castrate-sensitive and -resistant prostate cancer.Oncotarget. 2015 Dec 8;6(39):41976-87. doi: 10.18632/oncotarget.5659. Oncotarget. 2015. PMID: 26506516 Free PMC article.
-
Combination of sorafenib and enzalutamide as a potential new approach for the treatment of castration-resistant prostate cancer.Cancer Lett. 2017 Jan 28;385:108-116. doi: 10.1016/j.canlet.2016.10.036. Epub 2016 Nov 1. Cancer Lett. 2017. PMID: 27815035
-
Targeting persistent androgen receptor signaling in castration-resistant prostate cancer.Med Oncol. 2016 May;33(5):44. doi: 10.1007/s12032-016-0759-3. Epub 2016 Apr 4. Med Oncol. 2016. PMID: 27042852 Review.
-
Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level.Eur Urol. 2015 Mar;67(3):470-9. doi: 10.1016/j.eururo.2014.09.049. Epub 2014 Oct 8. Eur Urol. 2015. PMID: 25306226 Free PMC article. Review.
Cited by
-
Bardoxolone-Methyl (CDDO-Me) Suppresses Androgen Receptor and Its Splice-Variant AR-V7 and Enhances Efficacy of Enzalutamide in Prostate Cancer Cells.Antioxidants (Basel). 2020 Jan 12;9(1):68. doi: 10.3390/antiox9010068. Antioxidants (Basel). 2020. PMID: 31940946 Free PMC article.
-
Human DECR1 is an androgen-repressed survival factor that regulates PUFA oxidation to protect prostate tumor cells from ferroptosis.Elife. 2020 Jul 20;9:e54166. doi: 10.7554/eLife.54166. Elife. 2020. PMID: 32686647 Free PMC article.
-
Co-Targeting ErbB Receptors and the PI3K/AKT Axis in Androgen-Independent Taxane-Sensitive and Taxane-Resistant Human Prostate Cancer Cells.Cancers (Basel). 2022 Sep 23;14(19):4626. doi: 10.3390/cancers14194626. Cancers (Basel). 2022. PMID: 36230550 Free PMC article.
-
miR-5089-5p suppresses castration-resistant prostate cancer resistance to enzalutamide and metastasis via miR-5089-5p/SPINK1/ MAPK/MMP9 signaling.Aging (Albany NY). 2020 Jul 21;12(14):14418-14433. doi: 10.18632/aging.103485. Epub 2020 Jul 21. Aging (Albany NY). 2020. Retraction in: Aging (Albany NY). 2020 Oct 31;12(20):20930. doi: 10.18632/aging.104212 PMID: 32694237 Free PMC article. Retracted.
-
Systematically understanding the immunity leading to CRPC progression.PLoS Comput Biol. 2019 Sep 10;15(9):e1007344. doi: 10.1371/journal.pcbi.1007344. eCollection 2019 Sep. PLoS Comput Biol. 2019. PMID: 31504033 Free PMC article.
References
-
- Huggins C, Hodges C. The effect of castration, of estrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res. 1941;1:293–7. - PubMed
-
- Gioeli D, Mandell JW, Petroni GR, Frierson HF, Jr., Weber MJ. Activation of mitogen-activated protein kinase associated with prostate cancer progression. Cancer Res. 1999;59(2):279–84. Epub 1999/02/02. . - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Research Materials
