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Stalnecker CA, Grover KR, Edwards AC, et al. Concurrent inhibition of IGF1R and ERK increases pancreatic cancer sensitivity to autophagy inhibitors. Cancer Res. 2021;doi: 10.1158/0008-5472.CAN-21-1443.
Stalnecker, C. A., Grover, K. R., Edwards, A. C., Coleman, M. F., Yang, R., DeLiberty, J. M., Papke, B., Goodwin, C. M., Pierobon, M., Petricoin, E. F., Gautam, P., Wennerberg, K., Cox, A. D., Der, C. J., Hursting, S. D., & Bryant, K. L. (2021). Concurrent inhibition of IGF1R and ERK increases pancreatic cancer sensitivity to autophagy inhibitors. Cancer research, . https://doi.org/10.1158/0008-5472.CAN-21-1443
Stalnecker, Clint A, et al. "Concurrent inhibition of IGF1R and ERK increases pancreatic cancer sensitivity to autophagy inhibitors." Cancer research vol. (2021). doi: https://doi.org/10.1158/0008-5472.CAN-21-1443
Stalnecker CA, Grover KR, Edwards AC, Coleman MF, Yang R, DeLiberty JM, Papke B, Goodwin CM, Pierobon M, Petricoin EF, Gautam P, Wennerberg K, Cox AD, Der CJ, Hursting SD, Bryant KL. Concurrent inhibition of IGF1R and ERK increases pancreatic cancer sensitivity to autophagy inhibitors. Cancer Res. 2021 Dec 17; doi: 10.1158/0008-5472.CAN-21-1443. Epub 2021 Dec 17. PMID: 34921013.
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Cancer Res. 2021 Dec 17; doi: 10.1158/0008-5472.CAN-21-1443. Epub 2021 Dec 17.

Concurrent inhibition of IGF1R and ERK increases pancreatic cancer sensitivity to autophagy inhibitors.

Cancer research

Clint A Stalnecker, Kajal R Grover, Alexander C Edwards, Michael F Coleman, Runying Yang, Jonathan M DeLiberty, Bjoern Papke, Craig M Goodwin, Mariaelena Pierobon, Emanuel F Petricoin, Prson Gautam, Krister Wennerberg, Adrienne D Cox, Channing J Der, Stephen D Hursting, Kirsten L Bryant

Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill.
  2. Nutrition, University of North Carolina at Chapel Hill.
  3. Cell Biology and Physiology Curriculum, University of North Carolina at Chapel Hill.
  4. Dept. of Pharmacology, University of North Carolina at Chapel Hill.
  5. Center for Applied Proteomics and Molecular Medicine, George Mason University.
  6. Institute for Molecular Medicine Finland (FIMM), University of Helsinki.
  7. BRIC - Biotech Research & Innovation Centre, University of Copenhagen.
  8. Radiation Oncology and Pharmacology, University of North Carolina at Chapel Hill.
  9. Department of Pharmacology, University of North Carolina at Chapel Hill.
  10. Pharmacology, UNC-Chapel Hill [email protected].

PMID: 34921013 DOI: 10.1158/0008-5472.CAN-21-1443

Abstract

The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. Since KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant PDAC, and PDAC growth is reliant on autophagy. However, inhibition of autophagy as monotherapy using the lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy. To identify strategies that can improve PDAC sensitivity to HCQ, we applied a CRISPR-Cas9 loss-of-function screen and found that a top sensitizer was the receptor tyrosine kinase (RTK) insulin-like growth factor 1 receptor (IGF1R). Additionally, RPPA pathway activation mapping profiled the signaling pathways altered by CQ treatment. Activating phosphorylation of RTKs, including IGF1R, were common compensatory increases in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Co-targeting both IGF1R and pathways that antagonize autophagy, such as ERK-MAPK axis, was strongly synergistic. IGF1R and ERK inhibition converged on suppression of glycolysis, leading to enhanced dependence on autophagy. Accordingly, concurrent inhibition of IGF1R, ERK, and autophagy induced cytotoxicity in PDAC cell lines, and decreased viability in human PDAC organoids. In conclusion, targeting IGF1R together with ERK enhances the effectiveness of autophagy inhibitors in PDAC.

Copyright ©2021, American Association for Cancer Research.

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