In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

Akash K. Kaushik; Amy Tarangelo; Lindsey K. Boroughs; Mukundan Ragavan; Yuanyuan Zhang; Cheng Yang Wu; Xiangyi Li; Kristen Ahumada; Jui Chung Chiang; Vanina T. Tcheuyap; Faeze Saatchi; Quyen N. Do; Cissy Yong; Tracy Rosales; Christina Stevens; Aparna D. Rao; Brandon Faubert; Panayotis Pachnis; Lauren G. Zacharias; Hieu Vu; Feng Cai; Thomas P. Mathews; Giannicola Genovese; Barbara S. Slusher; Payal Kapur; Xiankai Sun; Matthew Merritt; James Brugarolas; Ralph J. DeBerardinis

doi:10.1126/sciadv.abp8293

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

Akash K. Kaushik, Amy Tarangelo, Lindsey K. Boroughs, Mukundan Ragavan, Yuanyuan Zhang, Cheng Yang Wu, Xiangyi Li, Kristen Ahumada, Jui Chung Chiang, Vanina T. Tcheuyap, Faeze Saatchi, Quyen N. Do, Cissy Yong, Tracy Rosales, Christina Stevens, Aparna D. Rao, Brandon Faubert, Panayotis Pachnis, Lauren G. Zacharias, Hieu VuFeng Cai, Thomas P. Mathews, Giannicola Genovese, Barbara S. Slusher, Payal Kapur, Xiankai Sun, Matthew Merritt, James Brugarolas, Ralph J. DeBerardinis

Genitourinary Medical Oncology

Research output: Contribution to journal › Article › peer-review

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Abstract

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.

Original language	English (US)
Article number	abp8293
Journal	Science Advances
Volume	8
Issue number	50
DOIs	https://doi.org/10.1126/sciadv.abp8293
State	Published - 2022

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Kaushik, A. K., Tarangelo, A., Boroughs, L. K., Ragavan, M., Zhang, Y., Wu, C. Y., Li, X., Ahumada, K., Chiang, J. C., Tcheuyap, V. T., Saatchi, F., Do, Q. N., Yong, C., Rosales, T., Stevens, C., Rao, A. D., Faubert, B., Pachnis, P., Zacharias, L. G., ... DeBerardinis, R. J. (2022). In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma. Science Advances, 8(50), Article abp8293. https://doi.org/10.1126/sciadv.abp8293

Kaushik, AK, Tarangelo, A, Boroughs, LK, Ragavan, M, Zhang, Y, Wu, CY, Li, X, Ahumada, K, Chiang, JC, Tcheuyap, VT, Saatchi, F, Do, QN, Yong, C, Rosales, T, Stevens, C, Rao, AD, Faubert, B, Pachnis, P, Zacharias, LG, Vu, H, Cai, F, Mathews, TP, Genovese, G, Slusher, BS, Kapur, P, Sun, X, Merritt, M, Brugarolas, J & DeBerardinis, RJ 2022, 'In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma', Science Advances, vol. 8, no. 50, abp8293. https://doi.org/10.1126/sciadv.abp8293

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title = "In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma",

abstract = "Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.",

author = "Kaushik, {Akash K.} and Amy Tarangelo and Boroughs, {Lindsey K.} and Mukundan Ragavan and Yuanyuan Zhang and Wu, {Cheng Yang} and Xiangyi Li and Kristen Ahumada and Chiang, {Jui Chung} and Tcheuyap, {Vanina T.} and Faeze Saatchi and Do, {Quyen N.} and Cissy Yong and Tracy Rosales and Christina Stevens and Rao, {Aparna D.} and Brandon Faubert and Panayotis Pachnis and Zacharias, {Lauren G.} and Hieu Vu and Feng Cai and Mathews, {Thomas P.} and Giannicola Genovese and Slusher, {Barbara S.} and Payal Kapur and Xiankai Sun and Matthew Merritt and James Brugarolas and DeBerardinis, {Ralph J.}",

note = "Publisher Copyright: {\textcopyright} 2022 The Authors.",

year = "2022",

doi = "10.1126/sciadv.abp8293",

language = "English (US)",

volume = "8",

journal = "Science Advances",

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T1 - In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

AU - Kaushik, Akash K.

AU - Tarangelo, Amy

AU - Boroughs, Lindsey K.

AU - Ragavan, Mukundan

AU - Zhang, Yuanyuan

AU - Wu, Cheng Yang

AU - Li, Xiangyi

AU - Ahumada, Kristen

AU - Chiang, Jui Chung

AU - Tcheuyap, Vanina T.

AU - Saatchi, Faeze

AU - Do, Quyen N.

AU - Yong, Cissy

AU - Rosales, Tracy

AU - Stevens, Christina

AU - Rao, Aparna D.

AU - Faubert, Brandon

AU - Pachnis, Panayotis

AU - Zacharias, Lauren G.

AU - Vu, Hieu

AU - Cai, Feng

AU - Mathews, Thomas P.

AU - Genovese, Giannicola

AU - Slusher, Barbara S.

AU - Kapur, Payal

AU - Sun, Xiankai

AU - Merritt, Matthew

AU - Brugarolas, James

AU - DeBerardinis, Ralph J.

PY - 2022

Y1 - 2022

N2 - Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.

AB - Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with [amide-15N]glutamine revealed persistent amidotransferase activity during glutaminase inhibition, and blocking these activities with the amidotransferase inhibitor JHU-083 also reduced tumor growth in both immunocompromised and immunocompetent mice. We conclude that ccRCC tumorgrafts catabolize glutamine via multiple pathways, perhaps explaining why it has been challenging to achieve therapeutic responses in patients by inhibiting glutaminase.

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DO - 10.1126/sciadv.abp8293

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AN - SCOPUS:85144174745

SN - 2375-2548

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JO - Science Advances

JF - Science Advances

IS - 50

M1 - abp8293

ER -

In vivo characterization of glutamine metabolism identifies therapeutic targets in clear cell renal cell carcinoma

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