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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI183474

Enhancing Gemcitabine Uptake by Promoting Dimerization of the ENT1 Transporter Improves Sarcoma Patient Response Rate

Aditya Ganju,1 Shyam Rao,2 Mark A. Dickson,3 Robert A. Lefkowitz,4 Chris Thompson,5 Jin Cheng,1 Katia Manova,6 Adriana Haimovitz-Friedman,7 Gary Schwartz,8 Zhigang Zhang,9 Zvi Fuks,5 William D. Tap,3 and Richard Kolesnick1

1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Cheng, J. in: PubMed | Google Scholar

1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Manova, K. in: PubMed | Google Scholar |

1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Schwartz, G. in: PubMed | Google Scholar

1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Zhang, Z. in: PubMed | Google Scholar

1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Fuks, Z. in: PubMed | Google Scholar

1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Tap, W. in: PubMed | Google Scholar

1Laboratory of Signal Transduction, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Department of Radiation Oncology, University of California, Davis Medical Center, Davis, United States of America

3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

4Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, United States of America

5Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Memorial Sloan Kettering Cancer Center, Cleveland, United States of America

8Department of Medicine, Case Western Reserve University, New York, United States of America

9Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, United States of America

Find articles by Kolesnick, R. in: PubMed | Google Scholar

Published September 3, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI183474.
Copyright © 2026, Ganju et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 3, 2026 - Version history
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Abstract

Transport of nucleoside chemotherapeutic drugs into tumor cells is primarily accomplished through Equilibrative Nucleoside Transporter 1 (ENT1), considered to be constitutively-active, redistributing drugs across lipid bilayers via facilitated diffusion. Here we discover that ENT1 is not constitutively-active but rather requires activation of acid sphingomyelinase (ASMase) by gemcitabine, generating ceramide-rich platforms (CRPs) on external plasma membranes of endothelial and tumor cells into which ENT1 inserts, dimerizing therein to functionalize transmembrane gemcitabine transport. Whereas sarcoma cells synthesize minimal ASMase, they take up gemcitabine poorly in vitro and in murine xenografts. A strategy designed to augment gemcitabine-induced ASMase secretion into the extravascular space by ASMase-rich neo-angiogenic cells, which then targets tumor cell plasma membranes, yields “bystander” CRPs on sarcoma cells and ENT1 insertion therein, conferring markedly-enhanced gemcitabine uptake and xenograft response. Engaging this biology in a prospective Phase II clinical trial in advanced sarcoma yielded robust volumetric changes in evaluated tumors that developed early and were often durable.

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Version history
  • Version 1 (September 3, 2026): In-Press Preview
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