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Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade

ABSTRACT: Prostate cancer (PCa) is the most common malignancy among western men and the second leading-cause of cancer related deaths. For men who develop metastatic, castration-resistant PCa (mCRPC), survival is limited, making the identification of novel therapies for mCRPC critical. Deficient lipid oxidation via carnitine palmitoyltransferase (CPT1) results in decreased growth and invasion, underscoring the role of lipid catabolism to fuel PCa growth. In fact, the CPT1A isoform is abundant in PCa, especially in those with high-grade tumors. Since lipid oxidation is stimulated by androgens, we have evaluated the synergistic effects of combining CPT1A inhibition and anti-androgen therapy. Mechanistically, we have found that decreased CPT1A expression is associated with decreased AKT content and activation, likely driven by a breakdown of membrane phospholipids and activation of the INPP5K phosphatase. This results in increased AR content and increased sensitivity to the anti-androgen enzalutamide. To better understand the clinical implications of this findings, we have evaluated fat oxidation inhibitors (etomoxir, ranolazine and perhexiline) in combination with enzalutamide in PCa cell models. We have observed a robust inhibitory effect of the combinations, including in enzalutamide-resistant cells and mouse TRAMPC1 cells, a more neuroendocrine PCa model. Lastly, using a xenograft mouse model, we have observed decreased tumor growth with a systemic combination treatment of enzalutamide and ranolazine. In conclusion, our results show that improved anti-cancer efficacy can be achieved by co-targeting the AR axis and fat oxidation via CPT1A, which may have clinical implications, especially in the mCRPC setting.

ORGANISM(S): Homo sapiens

PROVIDER: GSE83547 | GEO | 2017/06/10

SECONDARY ACCESSION(S): PRJNA326312

REPOSITORIES: GEO

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Project description:Prostate cancer (PCa) is the second most prevalent cancer and leading causes of death among men worldwide. Androgen deprivation is the first line of treatment for locally advanced and metastatic PCa. For men who develop metastatic castration-resistant PCa (mCRPC), survival is limited. Thus, there is a need to identify synergistic pathways to either prevent or re-sensitize the castration-resistant phenotype. PCa has a long natural history of development and there is a significant correlation between age, diet, metabolism and progress of PCa. We have previously reported that treating PCa cells with fatty acid oxidation inhibitors (FAOi) sensitizes them to androgen blockade. Here we set out to evaluate how the two disparate pathways: AR signaling and FAO, influence one another hoping to identify new therapeutic vulnerabilities. We used CRPC cell models (LNCaP-MDV-resistant, and LNCaP-C4-2), as well as the FAOi (etomoxir and ranolazine) and the antiandrogen enzalutamide (MDV3100). Cells were treated for 48 hours, followed by gene expression, androgen signaling and growth analysis. Both FAOi strongly suppressed the androgen response hallmark in MDV-res cells, and this was associated with a significant upregulation of the ATF3 gene. Interestingly, knockdown (KD) of ATF3 with shRNAs resulted in differential responses to FAOi in these genetically-related cells. In the MDV-resistant cells, ATF3 KD resulted in increased PSA expression with FAOi treatment. On the other hand, in the C4-2 cells, ATF3 KD resulted in decreased PSA expression with FAOi treatment. These results suggested that ATF3 is a convergent point for AR and FAO pathways and that is cell-context dependent, and its expression status could be exploited to sensitize PCa cells to MDV3100 and/or the FAOi. Cell growth and apoptosis assays confirmed that the LNCaP-derived ATF3 KD were more sensitive to MDV3100 and FAOi compared to control cells. Examination of patient databases revealed an inverse correlation between AR and ATF3, a low expression of ATF3 in advanced cancers and better disease-free survival in patients with high ATF3 expression. These data support the role for FAOi to re-sensitize CRPC to endocrine therapies. In conclusion, we have identified ATF3 as a modulator of FAO and AR signaling that has predictive value for clinical outcomes using FAOi in CRPC.

Project description:Background. Androgen receptor splice variant-7 (AR-V7) is a truncated form of the androgen receptor protein which lacks the ligand-binding domain, the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of AR-V7 in circulating tumor cells (CTCs) from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone. Methods. We used quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) to interrogate CTCs for the presence or absence of AR-V7 from prospectively enrolled patients with metastatic castration-resistant prostate cancer initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status and PSA response rates, PSA-progression-free-survival (PSA-PFS), clinical/radiographic-progression-free-survival (PFS), and overall survival (OS). Multivariable Cox regression analyses were performed to determine the independent effect of AR-V7 status on clinical outcomes. Results. Thirty-one enzalutamide-treated patients and thirty-one abiraterone-treated patients were enrolled, of which 38.7% and 19.4% had detectable AR-V7 from CTCs, respectively. Among men receiving enzalutamide, AR-V7–positive patients had inferior PSA response rates (0% vs 52.6%, P=0.004), PSA-PFS (median: 1.4 vs 6.0 months, P<0.001), PFS (median: 2.1 vs 6.1 months, P<0.001), and OS (median: 5.5 months vs not reached, P=0.002) compared to AR-V7–negative patients. Similarly, among men receiving abiraterone, AR-V7–positive patients had inferior PSA response rates (0% vs 68.0%, P=0.004), PSA-PFS (median: 1.3 months vs not reached, P<0.001), PFS (median: 2.3 months vs not reached, P<0.001), and OS (median: 10.6 months vs not reached, P=0.006). The negative prognostic impact of AR-V7 was maintained after adjusting for full-length-AR expression. Conclusions. Detection of AR-V7 in CTCs from patients with castration-resistant prostate cancer is associated with resistance to enzalutamide and abiraterone. A total of four metastatic castration-resistant prostate tumor samples from four patients were subjected to RNA-seq. Two samples were positive for androgen receptor splice variant 7 and the other two were negative for this variant.

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Lipid catabolism inhibition sensitizes prostate cancer cells to antiandrogen blockade

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