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

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.

• Authors: E Giovannetti, P A Zucali, Y G Assaraf, N Funel, M Gemelli, M Stark, E Thunnissen, Z Hou, I B Muller, E A Struys, M Perrino, G Jansen, L H Matherly, G J Peters
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 28 Issue 11 Pg. 2725-2732 (Nov 01 2017) ISSN: 1569-8041 [Electronic] England
• PMID: 28945836 (Publication Type: Journal Article)
• Copyright: © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Biomarkers, Tumor
• Folic Acid Antagonists
• Proton-Coupled Folate Transporter
• Reduced Folate Carrier Protein
• SLC19A1 protein, human
• SLC46A1 protein, human
• Pemetrexed
• Thymidylate Synthase

Topics

• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (metabolism)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Female
• Folic Acid Antagonists (therapeutic use)
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Male
• Mesothelioma (drug therapy, metabolism, pathology)
• Middle Aged
• Pemetrexed (therapeutic use)
• Pleural Neoplasms (drug therapy, metabolism, pathology)
• Prognosis
• Proton-Coupled Folate Transporter (metabolism)
• Reduced Folate Carrier Protein (metabolism)
• Survival Rate
• Thymidylate Synthase (metabolism)
• Tumor Cells, Cultured