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Ann Oncol. 2017 Nov 1;28(11):2725-2732. doi: 10.1093/annonc/mdx499.

Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools.

Author information

1
Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands; Cancer Pharmacology Lab, AIRC Start-Up Unit, Department of Translational Research and The New Technologies in Medicine and Surgery, University of Pisa, Pisa.
2
Department of Oncology, University of Milan, Humanitas Clinical and Research Hospital, Rozzano (Milan), Italy.
3
Department of Biology, Fred Wyszkowski Cancer Research Laboratory, Technion-Institute of Technology, Haifa, Israel.
4
Cancer Pharmacology Lab, AIRC Start-Up Unit, Department of Translational Research and The New Technologies in Medicine and Surgery, University of Pisa, Pisa.
5
Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
6
Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, USA.
7
Department of Clinical Chemistry, VU University Medical Center, Amsterdam.
8
Amsterdam Rheumatology and Immunology Center - Location VUmc, Amsterdam, The Netherlands.
9
Department of Medical Oncology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, The Netherlands. Electronic address: gj.peters@vumc.nl.

Abstract

Background:

Thymidylate synthase (TS) has a predictive role in pemetrexed treatment of mesothelioma; however, additional chemoresistance mechanisms are poorly understood. Here, we explored the role of the reduced-folate carrier (RFC/SLC19A1) and proton-coupled folate transporter (PCFT/SLC46A1) in antifolate resistance in mesothelioma.

Patients and methods:

PCFT, RFC and TS RNA and PCFT protein levels were determined by quantitative RT-PCR of frozen tissues and immunohistochemistry of tissue-microarrays, respectively, in two cohorts of pemetrexed-treated patients. Data were analyzed by t-test, Fisher's/log-rank test and Cox proportional models. The contribution of PCFT expression and PCFT-promoter methylation to pemetrexed activity were evaluated in mesothelioma cells and spheroids, through 5-aza-2'-deoxycytidine-mediated demethylation and siRNA-knockdown.

Results:

Pemetrexed-treated patients with low PCFT had significantly lower rates of disease control, and shorter overall survival (OS), in both the test (N = 73, 11.3 versus 20.1 months, P = 0.01) and validation (N = 51, 12.6 versus 30.3 months, P = 0.02) cohorts. Multivariate analysis confirmed PCFT-independent prognostic role. Low-PCFT protein levels were also associated with shorter OS. Patients with both low-PCFT and high-TS levels had the worst prognosis (OS, 5.5 months), whereas associations were neither found for RFC nor in pemetrexed-untreated patients. PCFT silencing reduced pemetrexed sensitivity, whereas 5-aza-2'-deoxycytidine overcame resistance.

Conclusions:

These findings identify for the first time PCFT as a novel mesothelioma prognostic biomarker, prompting prospective trials for its validation. Moreover, preclinical data suggest that targeting PCFT-promoter methylation might eradicate pemetrexed-resistant cells characterized by low-PCFT expression.

KEYWORDS:

PCFT; expression; malignant pleural mesothelioma; methylation; outcome; pemetrexed

PMID:
28945836
PMCID:
PMC5808668
DOI:
10.1093/annonc/mdx499
[Indexed for MEDLINE]
Free PMC Article

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