Biology and therapeutic applications of the proton-coupled folate transporter

ABSTRACT

Introduction

The proton-coupled folate transporter (PCFT; SLC46A1) was discovered in 2006 as the principal mechanism by which folates are absorbed in the intestine and the causal basis for hereditary folate malabsorption (HFM). In 2011, it was found that PCFT is highly expressed in many tumors. This stimulated interest in using PCFT for cytotoxic drug targeting, taking advantage of the substantial levels of PCFT transport and acidic pH conditions commonly associated with tumors.

Areas covered

We summarize the literature from 2006 to 2022 that explores the role of PCFT in the intestinal absorption of dietary folates and its role in HFM and as a transporter of folates and antifolates such as pemetrexed (Alimta) in relation to cancer. We provide the rationale for the discovery of a new generation of targeted pyrrolo[2,3-d]pyrimidine antifolates with selective PCFT transport and inhibitory activity toward de novo purine biosynthesis in solid tumors. We summarize the benefits of this approach to cancer therapy and exciting new developments in the structural biology of PCFT and its potential to foster refinement of active structures of PCFT-targeted anti-cancer drugs.

Expert opinion

We summarize the promising future and potential challenges of implementing PCFT-targeted therapeutics for HFM and a variety of cancers.

KEYWORDS:

• antifolate
• folate
• hereditary folate malabsorption
• one-carbon
• purine
• proton-coupled folate transporter

Article highlights

• The proton-coupled folate transporter (SLC46A1) is the principal mechanism by which folates are absorbed in the intestine and mutations in the SLC46A1 gene are the causal basis for hereditary folate malabsorption.

• The proton-coupled folate transporter is expressed in many tumors and is active under acidic conditions associated with tumors.

• New pyrrolo[2,3-d]pyrimidine antifolates are being discovered for cancer therapy with selective membrane transport via the proton-coupled folate transporter and as inhibitors of one-carbon metabolism.

• The recent structure of the proton-coupled folate transporter by cryo-electron microscopy provides new insights into transporter structure and function and should foster refinement of drugs for tumor-targeting based on their selective membrane transport.

• Future studies should emphasize further refining structures of drugs with selective transport by the proton-coupled folate transporter and inhibition of one-carbon metabolism, developing approaches for selectively increasing transporter levels or activity in tumors and for treating patients with hereditary folate malabsorption, and adapting discoveries in targeted drug delivery to include tumor imaging and key immune populations in the tumor microenvironment.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by NIH/NCI grant R01 CA053535 (Z Hou, LH Matherly), R01 CA250469 (LH Matherly, A Gangjee), T32 CA009531 (M Schneider), the Eunice and the Milton Ring Endowed Chair for Cancer Research (LH Matherly), and the Duquesne University Adrian Van Kaam Chair in Scholarly Excellence (A Gangjee).