Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As 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, reverse phase protein array pathway activation mapping profiled the signaling pathways altered by chloroquine (CQ) treatment. Activating phosphorylation of RTKs, including IGF1R, was a common compensatory increase in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Cotargeting 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. Significance: Compensatory upregulation of IGF1R and ERK- MAPK signaling limits the efficacy of autophagy inhibitors chloroquine and hydroxychloroquine, and their concurrent inhibition synergistically increases autophagy dependence and chloroquine sensitivity in pancreatic ductal adenocarcinoma.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Cancer Research |
| Vol/bind | 82 |
| Udgave nummer | 4 |
| Sider (fra-til) | 586-598 |
| Antal sider | 13 |
| ISSN | 0008-5472 |
| DOI | |
| Status | Udgivet - 2022 |
Bibliografisk note
Funding Information:
C.A. Stalnecker reports grants from NCI during the conduct of the study. A.C. Edwards reports grants from NIGMS (NIH) during the conduct of the study. B. Papke reports grants from Deutsche Forschungsgemeinschaft during the conduct of the study. M. Pierobon reports receiving of royalties from and being a consultant for TheraLink Technologies, Inc. E.F. Petricoin reports personal fees from Perthera, Inc., TheraLink Technologies, Inc., and Ceres Nanos-ciences, Inc. outside the submitted work. A.D. Cox reports grants from NIH, Pancreatic Cancer Action Network–AACR RAN, and personal fees from Eli Lilly during the conduct of the study; grants from NIH, Julie M. Brown and Christina Gianoplus Colon Cancer Foundation, and SpringWorks Therapeutics, and personal fees from Mirati Therapeutics outside the submitted work. C.J. Der reports grants and personal fees from Mirati Therapeutics, grants from SpringWorks Therapeutics, grants and personal fees from Deciphera Therapeutics, personal fees from Revolution Medicines, Jazz Therapeutics, Ribometrix, Eli Lilly, and Sanofi during the conduct of the study. K.L. Bryant reports grants from Pancreatic Cancer Action Network/AACR and grants from NCI during the conduct of the study; grants and nonfinancial support from SpringWorks Therapeutics and grants and nonfinancial support from Deciphera outside the submitted work. No disclosures were reported by the other authors.
Funding Information:
The authors thank K. Wood (Duke) for the CRISPR-Cas9 druggable genome library, A. Maitra (MD Anderson Cancer Center) for PDAC cell lines, D. Tuveson (Cold Spring Harbor Laboratory) for cell lines and organoids, and C. Kuo (Stanford University) for organoids. K.L. Bryant was supported by grants from the Pancreatic Cancer Action Network/AACR (15-70-25-BRYA), the Sky Foundation and from the NCI (P50CA196510 and R37CA251877). C.A. Stalnecker was supported by NCI T32CA009156 and F32CA232529. A.C. Edwards was supported by NIGMS T32GM119999. B. Papke was supported by the Deutsche Forschungsgemeinschaft (DFG PA 3051/1-1). C.M. Goodwin was supported by NCI T32CA009156 and F32CA221005. A.D. Cox and/or C.J. Der were supported by grants from the NCI (R01CA42978, R01CA175747, R01CA223775, P50CA196510, U01CA199235, P01CA203657, and R35CA232113), Pancreatic Cancer Action Network/AACR (15-90-25-DER), Department of Defense (W81XWH-15-1-0611), and the Lustgarten Foundation (388222). M.F. Coleman and S.D. Hursting were supported by NCI R35CA197627. M. Pierobon and E.F. Petricoin were supported by NCI P01CA203657. The Microscopy Services Laboratory and UNC Biomolecular NMR laboratory Core Facility were supported by P30 CA016086 Cancer Center Core Support grant to the UNC Lineberger Comprehensive Cancer Center.
Funding Information:
T32GM119999. B. Papke was supported by the Deutsche Forschungsgemeinschaft (DFG PA 3051/1-1). C.M. Goodwin was supported by NCI T32CA009156 and F32CA221005. A.D. Cox and/or C.J. Der were supported by grants from the NCI (R01CA42978, R01CA175747, R01CA223775, P50CA196510, U01CA199235, P01CA203657, and R35CA232113), Pancreatic Cancer Action Network/AACR (15-90-25-DER), Department of Defense (W81XWH-15-1-0611), and the Lustgarten Foundation (388222). M.F. Coleman and S.D. Hursting were supported by NCI R35CA197627. M. Pierobon and E.F. Petricoin were supported by NCI P01CA203657. The Microscopy Services Laboratory and UNC Biomolecular NMR
Funding Information:
The authors thank K. Wood (Duke) for the CRISPR-Cas9 druggable genome library, A. Maitra (MD Anderson Cancer Center) for PDAC cell lines, D. Tuveson (Cold Spring Harbor Laboratory) for cell lines and organoids, and C. Kuo (Stanford University) for organoids. K.L. Bryant was supported by grants from the Pancreatic Cancer Action Network/AACR (15-70-25-BRYA), the Sky Foundation and from the NCI (P50CA196510 and R37CA251877). C.A. Stalnecker was supported by NCI T32CA009156 and F32CA232529. A.C. Edwards was supported by NIGMS
Publisher Copyright:
© 2022 American Association for Cancer Research Inc.. All rights reserved.
Links
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8886214/pdf/nihms-1767243.pdf
Accepteret manuskript
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