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.
Highlights
Multiple myeloma (MM) is a malignancy of immunoglobulin-secreting plasma cells, and is considered the second most common hematologic malignancy
Both MTX and PDX caused significant reduction in cellular ATP levels in a subset of myeloma cell lines, with pralatrexate appearing about a log more potent in sensitive lines compared to MTX
No cell line exhibited sensitivity to only one antifolate, with all lines either sensitive to MTX and pralatrexate, or resistant to both agents The myeloma cell lines appeared to segregate into two distinct groups based on their patterns of sensitivity
Summary
Multiple myeloma (MM) is a malignancy of immunoglobulin-secreting plasma cells, and is considered the second most common hematologic malignancy. Despite the introduction of many effective drugs over the past decades, the disease is widely considered incurable [1]. Incomplete eradication of the disease has been attributed, at least in part, to heterogeneity and clonal evolution of the malignant plasma cell population [2, 3]. Recent studies utilizing advances in single-cell sequencing and whole exome profiling have identified subclonal tumor cell populations present at initial treatment which expand over time, producing increasingly drug resistant phenotypes [4]. Identification of functional biomarkers which correlate with sensitivity or resistance to a particular drug or class of drugs is a principle component of the “precision medicine” approach to treat many malignant diseases, including relapsed multiple myeloma [5]. The integration of novel agents into a tailored treatment strategy based on the patients’ disease biology could increase the probability of favorable outcome
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