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Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer

View ORCID ProfileChun-Hao Pan, Nina V. Chaika, Robert Tseng, Md Afjalus Siraj, Bo Chen, Katie L. Donnelly, Michael Horowitz, Cindy V. Leiton, Sumedha Chowdhury, Lucia Roa-Peña, Lyanne Oblein, Natalia Marchenko, Pankaj K. Singh, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos
doi: https://doi.org/10.1101/2022.08.24.504873
Chun-Hao Pan
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
2Molecular and Cellular Biology Graduate Program, Stony Brook University, Stony Brook, NY, US
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  • ORCID record for Chun-Hao Pan
Nina V. Chaika
3Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, US
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Robert Tseng
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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Md Afjalus Siraj
4Department of Therapeutic Radiology and Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, US
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Bo Chen
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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Katie L. Donnelly
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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Michael Horowitz
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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Cindy V. Leiton
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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Sumedha Chowdhury
4Department of Therapeutic Radiology and Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, US
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Lucia Roa-Peña
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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Lyanne Oblein
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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Natalia Marchenko
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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Pankaj K. Singh
3Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, US
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  • For correspondence: pankaj-singh@ouhsc.edu Kenneth.Shroyer@stonybrookmedicine.edu luisa.escobar-hoyos@yale.edu
Kenneth R. Shroyer
1Department of Pathology, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY, US
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  • For correspondence: pankaj-singh@ouhsc.edu Kenneth.Shroyer@stonybrookmedicine.edu luisa.escobar-hoyos@yale.edu
Luisa F. Escobar-Hoyos
4Department of Therapeutic Radiology and Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, US
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  • For correspondence: pankaj-singh@ouhsc.edu Kenneth.Shroyer@stonybrookmedicine.edu luisa.escobar-hoyos@yale.edu
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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death. We previously reported keratin 17 (K17) as a novel negative prognostic and predictive biomarker, whose overexpression confers the resistance to chemotherapies. Here, we investigated the mechanisms of chemoresistance and tumor-specific vulnerabilities that can be exploited for targeted therapies for K17-expressing PDAC. Unbiased metabolomic studies in isogenic PDAC models identified several key metabolic pathways that are upregulated in the presence of K17. We demonstrate that K17 increases pyrimidine biosynthesis, a pathway that has been linked to chemoresistance. Patient dataset analysis revealed that K17 expression and enzymes involved in pyrimidine, but not purine, de novo biosynthesis is associated with shorter patient survival. Rescue experiments showed that deoxycytidine (dC) and deoxythymidine (dT) were sufficient to promote resistance to Gemcitabine (a dC analog) and 5-fluorouracil (a dT analog), respectively. Furthermore, K17-expressing cells were more sensitive to Brequinar, a specific inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine biosynthetic pathway. Targeting DHODH by small interfering RNA or by Brequinar with Gemcitabine synergistically inhibited the viability of K17-positive PDAC cells. Importantly, the combination of Gemcitabine and Brequinar significantly inhibited the growth of K17-expressing tumors and extended survival of mice bearing K17-expressing PDACs. Overall, we identified a novel pathway of chemoresistance and a metabolic target of which could lead to the development of a biomarker-based therapy for K17-expressing PDAC.

Competing Interest Statement

KRS and LFE-H are members of the Scientific Advisory Board for KDx Diagnostics Inc.

Footnotes

  • Additional information, Financial support: This work was supported by grants from the Pancreatic Cancer Action Network Translational Research Grant; grant number 18-65-SHRO (K.R.S), NCI K99-R00 CA226342-01 (L.F.E-H), Hirshberg Foundation (L.F.E-H), Damon Runyon Foundation (Innovator Award-L.F.E-H), an AACR Award for Pancreatic Cancer Research, in honor of Ruth Bader Ginsburg (L.F.E-H)., and a Bahl IDEA Award from Stony Brook Univeristy (K.R.S.).

  • Conflicts of interest: KRS and LFE-H are members of the Scientific Advisory Board for KDx Diagnostics Inc.

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Posted August 26, 2022.
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Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer
Chun-Hao Pan, Nina V. Chaika, Robert Tseng, Md Afjalus Siraj, Bo Chen, Katie L. Donnelly, Michael Horowitz, Cindy V. Leiton, Sumedha Chowdhury, Lucia Roa-Peña, Lyanne Oblein, Natalia Marchenko, Pankaj K. Singh, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos
bioRxiv 2022.08.24.504873; doi: https://doi.org/10.1101/2022.08.24.504873
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Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer
Chun-Hao Pan, Nina V. Chaika, Robert Tseng, Md Afjalus Siraj, Bo Chen, Katie L. Donnelly, Michael Horowitz, Cindy V. Leiton, Sumedha Chowdhury, Lucia Roa-Peña, Lyanne Oblein, Natalia Marchenko, Pankaj K. Singh, Kenneth R. Shroyer, Luisa F. Escobar-Hoyos
bioRxiv 2022.08.24.504873; doi: https://doi.org/10.1101/2022.08.24.504873

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