Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer

Kirsten L. Bryant, Clint A. Stalnecker, Daniel Zeitouni, Jennifer E. Klomp, Sen Peng, Andrey P. Tikunov, Venugopal Gunda, Mariaelena Pierobon, Andrew M. Waters, Samuel D. George, Garima Tomar, Björn Papke, G. Aaron Hobbs, Liang Yan, Tikvah K. Hayes, J. Nathaniel Diehl, Gennifer D. Goode, Nina V. Chaika, Yingxue Wang, Guo Fang Zhang & 11 others Agnieszka K. Witkiewicz, Erik S. Knudsen, Emanuel F. Petricoin, Pankaj K. Singh, Jeffrey M. Macdonald, Nhan Tran, Costas A. Lyssiotis, Haoqiang Ying, Alec C. Kimmelman, Adrienne D. Cox, Channing J. Der

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by KRAS- and autophagy-dependent tumorigenic growth, but the role of KRAS in supporting autophagy has not been established. We show that, to our surprise, suppression of KRAS increased autophagic flux, as did pharmacological inhibition of its effector ERK MAPK. Furthermore, we demonstrate that either KRAS suppression or ERK inhibition decreased both glycolytic and mitochondrial functions. We speculated that ERK inhibition might thus enhance PDAC dependence on autophagy, in part by impairing other KRAS- or ERK-driven metabolic processes. Accordingly, we found that the autophagy inhibitor chloroquine and genetic or pharmacologic inhibition of specific autophagy regulators synergistically enhanced the ability of ERK inhibitors to mediate antitumor activity in KRAS-driven PDAC. We conclude that combinations of pharmacologic inhibitors that concurrently block both ERK MAPK and autophagic processes that are upregulated in response to ERK inhibition may be effective treatments for PDAC.

Original languageEnglish (US)
Pages (from-to)628-640
Number of pages13
JournalNature Medicine
Volume25
Issue number4
DOIs
StatePublished - Apr 1 2019

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Autophagy
Chloroquine
Pancreatic Neoplasms
Fluxes
Adenocarcinoma
Pharmacology
Growth

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Bryant, K. L., Stalnecker, C. A., Zeitouni, D., Klomp, J. E., Peng, S., Tikunov, A. P., ... Der, C. J. (2019). Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nature Medicine, 25(4), 628-640. https://doi.org/10.1038/s41591-019-0368-8

Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. / Bryant, Kirsten L.; Stalnecker, Clint A.; Zeitouni, Daniel; Klomp, Jennifer E.; Peng, Sen; Tikunov, Andrey P.; Gunda, Venugopal; Pierobon, Mariaelena; Waters, Andrew M.; George, Samuel D.; Tomar, Garima; Papke, Björn; Hobbs, G. Aaron; Yan, Liang; Hayes, Tikvah K.; Diehl, J. Nathaniel; Goode, Gennifer D.; Chaika, Nina V.; Wang, Yingxue; Zhang, Guo Fang; Witkiewicz, Agnieszka K.; Knudsen, Erik S.; Petricoin, Emanuel F.; Singh, Pankaj K.; Macdonald, Jeffrey M.; Tran, Nhan; Lyssiotis, Costas A.; Ying, Haoqiang; Kimmelman, Alec C.; Cox, Adrienne D.; Der, Channing J.

In: Nature Medicine, Vol. 25, No. 4, 01.04.2019, p. 628-640.

Research output: Contribution to journalArticle

Bryant, KL, Stalnecker, CA, Zeitouni, D, Klomp, JE, Peng, S, Tikunov, AP, Gunda, V, Pierobon, M, Waters, AM, George, SD, Tomar, G, Papke, B, Hobbs, GA, Yan, L, Hayes, TK, Diehl, JN, Goode, GD, Chaika, NV, Wang, Y, Zhang, GF, Witkiewicz, AK, Knudsen, ES, Petricoin, EF, Singh, PK, Macdonald, JM, Tran, N, Lyssiotis, CA, Ying, H, Kimmelman, AC, Cox, AD & Der, CJ 2019, 'Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer', Nature Medicine, vol. 25, no. 4, pp. 628-640. https://doi.org/10.1038/s41591-019-0368-8
Bryant KL, Stalnecker CA, Zeitouni D, Klomp JE, Peng S, Tikunov AP et al. Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. Nature Medicine. 2019 Apr 1;25(4):628-640. https://doi.org/10.1038/s41591-019-0368-8
Bryant, Kirsten L. ; Stalnecker, Clint A. ; Zeitouni, Daniel ; Klomp, Jennifer E. ; Peng, Sen ; Tikunov, Andrey P. ; Gunda, Venugopal ; Pierobon, Mariaelena ; Waters, Andrew M. ; George, Samuel D. ; Tomar, Garima ; Papke, Björn ; Hobbs, G. Aaron ; Yan, Liang ; Hayes, Tikvah K. ; Diehl, J. Nathaniel ; Goode, Gennifer D. ; Chaika, Nina V. ; Wang, Yingxue ; Zhang, Guo Fang ; Witkiewicz, Agnieszka K. ; Knudsen, Erik S. ; Petricoin, Emanuel F. ; Singh, Pankaj K. ; Macdonald, Jeffrey M. ; Tran, Nhan ; Lyssiotis, Costas A. ; Ying, Haoqiang ; Kimmelman, Alec C. ; Cox, Adrienne D. ; Der, Channing J. / Combination of ERK and autophagy inhibition as a treatment approach for pancreatic cancer. In: Nature Medicine. 2019 ; Vol. 25, No. 4. pp. 628-640.
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AU - Tikunov, Andrey P.

AU - Gunda, Venugopal

AU - Pierobon, Mariaelena

AU - Waters, Andrew M.

AU - George, Samuel D.

AU - Tomar, Garima

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AU - Knudsen, Erik S.

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