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, Agnieszka K Witkiewicz, Erik S Knudsen, Emanuel F Petricoin 3rd, Pankaj K Singh, Jeffrey M Macdonald, Nhan L Tran, Costas A Lyssiotis, Haoqiang Ying, Alec C Kimmelman, Adrienne D Cox, Channing J Der, 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, Agnieszka K Witkiewicz, Erik S Knudsen, Emanuel F Petricoin 3rd, Pankaj K Singh, Jeffrey M Macdonald, Nhan L Tran, Costas A Lyssiotis, Haoqiang Ying, Alec C Kimmelman, Adrienne D Cox, Channing J Der
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.
Conflict of interest statement
Competing interests
C.J.D. is on the Scientific Advisory Board of Mirati Therapeutics. A.C.K. has financial interests in Vescor Therapeutics, LLC. A.C.K. is an inventor on patents pertaining to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, and the autophagic control of iron metabolism. A.C.K. is on the Scientific Advisory Board of Cornerstone/Rafael Pharmaceuticals.
Figures
![Extended Data Fig. 1. Genetic suppression of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0007.jpg)
![Extended Data Fig. 2. Pharmacological inhibition of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0008.jpg)
![Extended Data Fig. 3. ERK inhibition influences…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0009.jpg)
![Extended Data Fig. 4. Genetic silencing of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0010.jpg)
![Extended Data Fig. 5. Genetic silencing of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0011.jpg)
![Extended Data Fig. 6. Genetic silencing of…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0012.jpg)
![Extended Data Fig. 7. ERK and MEK…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0013.jpg)
![Extended Data Fig. 8. ERK inhibition synergizes…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0014.jpg)
![Extended Data Fig. 9. ERK inhibition synergizes…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0015.jpg)
![Extended Data Fig. 10. Inhibition of upstream…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0016.jpg)
![Fig. 1. KRAS suppression increases autophagic flux…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0001.jpg)
![Fig. 2. Pharmacological inhibition of ERK1/ERK2 increases…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0002.jpg)
![Fig. 3. Pharmacological inhibition of ERK1/ERK2 increases…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0003.jpg)
![Fig. 4. ERK inhibition and KRAS silencing…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0004.jpg)
![Fig. 5. Dual inhibition of ERK signaling…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0005.jpg)
![Fig. 6. Synergy with ERK inhibition is…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6484853/bin/nihms-1023935-f0006.jpg)
Source: PubMed