Oncotarget

Research Papers:

The anti-tumor activity of pralatrexate (PDX) correlates with the expression of RFC and DHFR mRNA in preclinical models of multiple myeloma

Cristina Kinahan _, Michael A. Mangone _, Luigi Scotto, Michele Visentin, Enrica Marchi, Hearn Jay Cho and Owen A. O’Connor

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Oncotarget. 2020; 11:1576-1589. https://doi.org/10.18632/oncotarget.27516

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Abstract

Cristina Kinahan1,*, Michael A. Mangone1,*, Luigi Scotto1, Michele Visentin2, Enrica Marchi1, Hearn Jay Cho3 and Owen A. O’Connor1

1 Columbia University Medical Center, Center for Lymphoid Malignancies, New York, NY, USA

2 Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

3 Department of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

* Co-first authors

Correspondence to:

Cristina Kinahan,email: Cristina.kinahan@gmail.com
Michael A. Mangone,email: mikemangone@gmail.com

Keywords: antifolate; multiple myeloma; pralatrexate; biomarker; reduced folate carrier (RFC)

Abbreviations: PDX: pralatrexate; MTX: methotrexate; MM: multiple myeloma; RFC: reduced folate carrier

Received: October 29, 2019     Accepted: February 17, 2020     Published: May 05, 2020

ABSTRACT

Multiple myeloma (MM) is the second most common hematologic malignancy. While major advances have been made in the disease, it is still incurable. Although antifolate-based drugs are not commonly used to treat myeloma, new generation analogs with distinct patterns of preclinical and clinical activity may offer an opportunity to identify new classes of potentially active drugs. Pralatrexate (PDX), which was approved for the treatment of relapsed or refractory peripheral T-cell lymphoma in 2009, may be one such drug. Pralatrexate exhibits a potency and pattern of activity distinct from its predecessors like methotrexate (MTX). We sought to understand the activity and mechanisms of resistance of multiple myeloma to these drugs, which could also offer potential strategies for selective use of the drug. We demonstrate that PDX and MTX both induce a significant decrease in cell viability in the low nanomolar range, with PDX exhibiting a more potent effect. We identified a series of myeloma cell lines exhibiting markedly different patterns of sensitivity to the drugs, with some lines frankly resistant, and others exquisitely sensitive. These differences were largely attributed to the basal RFC (Reduced Folate Carrier) mRNA expression levels. RFC mRNA expression correlated directly with rates of drug uptake, with the most sensitive lines exhibiting the most significant intracellular accumulation of pralatrexate. This mechanism explains the widely varying patterns of sensitivity and resistance to pralatrexate in multiple myeloma cell lines. These findings could have implications for this class of drugs and their role in the treatment of multiple myeloma.


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