Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer

Min-Sik Lee, Courtney Dennis, Insia Naqvi, Lucas Dailey, Alireza Lorzadeh, George Ye, Tamara Zaytouni, Ashley Adler, Daniel S. Hitchcock, Lin Lin, Megan T. Hoffman, Aladdin M. Bhuiyan, Jaimie L. Barth, Miranda E. Machacek, Mari Mino-Kenudson, Stephanie K. Dougan, Unmesh Jadhav, Clary B. Clish and Nada Y. Kalaany ()
Additional contact information
Min-Sik Lee: Boston Children’s Hospital
Courtney Dennis: Broad Institute of MIT and Harvard
Insia Naqvi: Boston Children’s Hospital
Lucas Dailey: Broad Institute of MIT and Harvard
Alireza Lorzadeh: University of Southern California
George Ye: University of Southern California
Tamara Zaytouni: Boston Children’s Hospital
Ashley Adler: Boston Children’s Hospital
Daniel S. Hitchcock: Broad Institute of MIT and Harvard
Lin Lin: Boston Children’s Hospital
Megan T. Hoffman: Dana-Farber Cancer Institute
Aladdin M. Bhuiyan: Dana-Farber Cancer Institute
Jaimie L. Barth: Massachusetts General Hospital
Miranda E. Machacek: Massachusetts General Hospital
Mari Mino-Kenudson: Massachusetts General Hospital
Stephanie K. Dougan: Dana-Farber Cancer Institute
Unmesh Jadhav: University of Southern California
Clary B. Clish: Broad Institute of MIT and Harvard
Nada Y. Kalaany: Boston Children’s Hospital

Nature, 2023, vol. 616, issue 7956, 339-347

Abstract: Abstract There is a need to develop effective therapies for pancreatic ductal adenocarcinoma (PDA), a highly lethal malignancy with increasing incidence1 and poor prognosis2. Although targeting tumour metabolism has been the focus of intense investigation for more than a decade, tumour metabolic plasticity and high risk of toxicity have limited this anticancer strategy3,4. Here we use genetic and pharmacological approaches in human and mouse in vitro and in vivo models to show that PDA has a distinct dependence on de novo ornithine synthesis from glutamine. We find that this process, which is mediated through ornithine aminotransferase (OAT), supports polyamine synthesis and is required for tumour growth. This directional OAT activity is usually largely restricted to infancy and contrasts with the reliance of most adult normal tissues and other cancer types on arginine-derived ornithine for polyamine synthesis5,6. This dependency associates with arginine depletion in the PDA tumour microenvironment and is driven by mutant KRAS. Activated KRAS induces the expression of OAT and polyamine synthesis enzymes, leading to alterations in the transcriptome and open chromatin landscape in PDA tumour cells. The distinct dependence of PDA, but not normal tissue, on OAT-mediated de novo ornithine synthesis provides an attractive therapeutic window for treating patients with pancreatic cancer with minimal toxicity.

Date: 2023
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DOI: 10.1038/s41586-023-05891-2

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