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

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


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.

MeSH terms

  • 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
  • Mesothelioma / metabolism
  • Mesothelioma / pathology*
  • Middle Aged
  • Pemetrexed / therapeutic use*
  • Pleural Neoplasms / drug therapy
  • Pleural Neoplasms / metabolism
  • Pleural Neoplasms / pathology*
  • Prognosis
  • Proton-Coupled Folate Transporter / metabolism*
  • Reduced Folate Carrier Protein / metabolism*
  • Survival Rate
  • Thymidylate Synthase / metabolism
  • Tumor Cells, Cultured


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