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

Giovannetti, Elisa; Zucali, Paolo Andrea; Assaraf, Yehuda G.; Funel, Niccola; Gemelli, M; Stark, Michal; Thunnissen, Erik; Hou, Zhanjun; Muller, Ittai B.; Struys, Eduard A.; Perrino, Matteo; Jansen, Gerrit; Matherly, Larry H.; Peters, Godefridus J.

doi:10.1093/annonc/mdx499

Cited by 37 publications

(58 citation statements)

References 23 publications

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“…3,4,18 PCFT is expressed in human tumors with particularly high levels in NSCLC, 19 EOC, 11 and malignant pleural mesothelioma. 20 PCFT functions in the cellular uptake of folates and antifolates at acidic pHs characterizing the microenvironments of many solid tumors. 3,21 …”

Section: Introductionmentioning

confidence: 99%

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

et al. 2018

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Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidine analogues 7–12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) α and β or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11, and 12 showed increased in vitro antiproliferative activities (~11-fold) over the nonfluorinated analogues 2, 3, 5, and 6 toward engineered Chinese hamster ovary and HeLa cells expressing FRs or PCFT. Compounds 8, 9, 11, and 12 also inhibited proliferation of IGROV1 and A2780 epithelial ovarian cancer cells; in IGROV1 cells with knockdown of FRα, 9, 11, and 12 showed sustained inhibition associated with uptake by PCFT. All compounds inhibited glycinamide ribonucleotide formyltransferase, a key enzyme in the de novo purine biosynthesis pathway. Molecular modeling studies validated in vitro cell-based results. NMR evidence supports the presence of an intramolecular fluorine−hydrogen bond. Potent in vivo efficacy of 11 was established with IGROV1 xenografts in severe compromised immunodeficient mice.

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Section: Introductionmentioning

confidence: 99%

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

et al. 2018

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“…Although some novel anti-cancer drugs have been successful and have yielded improvements for cancer patients, they remain imperfect ( Fojo and Parkinson, 2010 ; Groenendijk and Bernards, 2014 ), and have also become a financial burden for the health system ( Kantarjian et al, 2013 ; Aggarwal, 2010 ; Prasad and Mailankody, 2017 ; Fojo and Parkinson, 2010 ). During the course of treatment, most patients sooner or later also receive classical chemotherapy including platinum drugs, topoisomerase inhibitors, microtubule-targeting agents or antimetabolites as part of standard care ( Gonen and Assaraf, 2012 ; Giovannetti et al, 2017 ). Their clinical use is based on empirical experience.…”

Section: Introductionmentioning

confidence: 99%

New tools for old drugs: Functional genetic screens to optimize current chemotherapy

Gerhards

Rottenberg

2018

Drug Resistance Updates

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Despite substantial advances in the treatment of various cancers, many patients still receive anti-cancer therapies that hardly eradicate tumor cells but inflict considerable side effects. To provide the best treatment regimen for an individual patient, a major goal in molecular oncology is to identify predictive markers for a personalized therapeutic strategy. Regarding novel targeted anti-cancer therapies, there are usually good markers available. Unfortunately, however, targeted therapies alone often result in rather short remissions and little cytotoxic effect on the cancer cells. Therefore, classical chemotherapy with frequent long remissions, cures, and a clear effect on cancer cell eradication remains a corner stone in current anti-cancer therapy. Reliable biomarkers which predict the response of tumors to classical chemotherapy are rare, in contrast to the situation for targeted therapy. For the bulk of cytotoxic therapeutic agents, including DNA-damaging drugs, drugs targeting microtubules or antimetabolites, there are still no reliable biomarkers used in the clinic to predict tumor response. To make progress in this direction, meticulous studies of classical chemotherapeutic drug action and resistance mechanisms are required. For this purpose, novel functional screening technologies have emerged as successful technologies to study chemotherapeutic drug response in a variety of models. They allow a systematic analysis of genetic contributions to a drug-responsive or −sensitive phenotype and facilitate a better understanding of the mode of action of these drugs. These functional genomic approaches are not only useful for the development of novel targeted anti-cancer drugs but may also guide the use of classical chemotherapeutic drugs by deciphering novel mechanisms influencing a tumor’s drug response. Moreover, due to the advances of 3D organoid cultures from patient tumors and in vivo screens in mice, these genetic screens can be applied using conditions that are more representative of the clinical setting. Patient-derived 3D organoid lines furthermore allow the characterization of the “essentialome”, the specific set of genes required for survival of these cells, of an individual tumor, which could be monitored over the course of treatment and help understanding how drug resistance evolves in clinical tumors. Thus, we expect that these functional screens will enable the discovery of novel cancer-specific vulnerabilities, and through clinical validation, move the field of predictive biomarkers forward. This review focuses on novel advanced techniques to decipher the interplay between genetic alterations and drug response.

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“…This may be particularly relevant to pemetrexed, an agent that has a high affinity for this transporter, and may be the reason why tumor cells that develop resistance to methotrexate (MTX) owing to loss of reduced folate carrier function, retain sensitivity to pemetrexed (Zhao et al, 2004b;Chattopadhyay et al, 2006). Low expression of PCFT strongly correlates with poor outcome in patients with mesothelioma treated with pemetrexed (Giovannetti et al, 2017). PCFT is the sole carrier-mediated route of transport of a new generation of folate analogs that are inhibitors of purine synthesis (Matherly et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Concentrative Transport of Antifolates Mediated by the Proton-Coupled Folate Transporter (SLC46A1); Augmentation by a HEPES Buffer

et al. 2018

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The proton-coupled folate transporter (PCFT) is ubiquitously expressed in solid tumors to which it delivers antifolates, particularly pemetrexed, into cancer cells. Studies of PCFT-mediated transport, to date, have focused exclusively on the influx of folates and antifolates. This article addresses the impact of PCFT on concentrative transport, critical to the formation of the active polyglutamate congeners, and at pH levels relevant to the tumor microenvironment. An HeLa-derived cell line was employed, in which folate-specific transport was mediated exclusively by PCFT. At pH 7.0, there was a substantial chemical gradient for methotrexate that decreased as the extracellular pH was increased. A chemical gradient was still detected at pH 7.4 in the usual HEPES-based transport buffer in contrast to what was observed in a bicarbonate/CO-buffered medium. This antifolate gradient correlated with an alkaline intracellular pH in the former (pH 7.85), but not the latter (pH 7.39), buffer and was abolished by the protonophore carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone. The gradient in HEPES buffer at pH 7.4 was the result of the activity of Na/H exchanger(s); it was eliminated by inhibitors of Na/H exchanger (s) or Na/K ATPase. An antifolate chemical gradient was also detected in bicarbonate buffer at pH 6.9 versus 7.4, also suppressed by carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone. When the membrane potential is considered, PCFT generates substantial transmembrane electrochemical-potential gradients at extracellular pH levels relevant to the tumor microenvironment. The augmentation of intracellular pH, when cells are in a HEPES buffer, should be taken into consideration in studies that encompass all proton-coupled transporter families.

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

Cited by 37 publications

References 23 publications

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

Fluorine-Substituted Pyrrolo[2,3-d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor α and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis

New tools for old drugs: Functional genetic screens to optimize current chemotherapy

Concentrative Transport of Antifolates Mediated by the Proton-Coupled Folate Transporter (SLC46A1); Augmentation by a HEPES Buffer

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