TY - JOUR
T1 - The KRAS-regulated kinome identifies WEE1 and ERK coinhibition as a potential therapeutic strategy in KRAS-mutant pancreatic cancer
AU - Nathaniel Diehl, J.
AU - Klomp, Jennifer E.
AU - Snare, Kayla R.
AU - Hibshman, Priya S.
AU - Blake, Devon R.
AU - Kaiser, Zane D.
AU - Gilbert, Thomas S.K.
AU - Baldelli, Elisa
AU - Pierobon, Mariaelena
AU - Papke, Björn
AU - Yang, Runying
AU - Hodge, Richard G.
AU - Rashid, Naim U.
AU - Petricoin, Emanuel F.
AU - Herring, Laura E.
AU - Graves, Lee M.
AU - Cox, Adrienne D.
AU - Der, Channing J.
N1 - Funding Information:
Funding and additional information—This work was supported by grants (to C. J. D. and A. D. C.) from the National Institutes of Health/National Cancer Institute (NCI) (CA42978, CA179193, CA175747, and CA199235) and the Pancreatic Cancer Action Network–American Association for Cancer Research. C. J. D. was also supported by grants from the Department of Defense (W81XWH-15-1-0611) and Lustgarten Pancreatic Cancer Foundation (388222). J. N. D. was supported by fellowships from the Slomo and Cindy Silvian Foundation, NCI F30CA243253, and NCI T32CA071341. J. E. K. was supported by NCI T32CA009156, F32 CA239328, and American Cancer Society (PF-20-069). D. R. B. was supported by NCI T32CA071341 and F31CA216965. P. S. H. was supported by NCI T32CA071341. R. G. H. was supported by a grant from Debbie’s Dream Foundation.
Funding Information:
Conflict of interest—C. J. D. is a consultant/advisory board member for Anchiano Therapeutics, Deciphera Pharmaceuticals, Mirati Therapeutics, and Revolution Medicines. C. J. D. has received research funding support from SpringWorks Therapeutics, Mirati Therapeutics, and Deciphera Pharmaceuticals and has consulted for Ribometrix, Sanofi, Jazz Therapeutics, Turning Point Therapeutics, and Eli Lilly. A. D. C. has consulted for Eli Lilly and Mirati Therapeutics. E. F. P. and M. P. are inventors on US government and university assigned patents and patent applications that cover aspects of the technologies discussed such as the reverse phase protein microarrays. As inventors, they are entitled to receive royalties as provided by US Law and George Mason University policy. M. P. and E. F. P. receive royalties from and are consultants of TheraLink Technologies, Inc. E. F. P. is a shareholder of TheraLink Technologies, Inc. and a shareholder and consultant of Perthera, Inc. All other authors no conflicts of interest with the contents of this article.
Funding Information:
Acknowledgments—We thank Sarah Howard for her assistance in article preparation. The University of North Carolina Flow Cytometry Core Facility and the Michael Hooker Proteomics Center are supported in part by P30 CA016086 Cancer Center Core Support Grant to the University of North Carolina Lineberger Comprehensive Cancer Center.
Publisher Copyright:
© 2021 American Society for Biochemistry and Molecular Biology Inc.. All rights reserved.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRASregulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines and then applied multiplexed inhibitor bead/MS to monitor changes in kinase activity and/or expression. We hypothesized that depletion of KRAS would result in downregulation of kinases required for KRAS-mediated transformation and in upregulation of other kinases that could potentially compensate for the deleterious consequences of the loss of KRAS. We identified 15 upregulated and 13 downregulated kinases in common across the panel of cell lines. In agreement with our hypothesis, all 15 of the upregulated kinases have established roles as cancer drivers (e.g., SRC, TGF-β1, ILK), and pharmacological inhibition of one of these upregulated kinases, DDR1, suppressed PDAC growth. Interestingly, 11 of the 13 downregulated kinases have established driver roles in cell cycle progression, particularly in mitosis (e.g., WEE1, Aurora A, PLK1). Consistent with a crucial role for the downregulated kinases in promoting KRAS-driven proliferation, we found that pharmacological inhibition of WEE1 also suppressed PDAC growth. The unexpected paradoxical activation of ERK upon WEE1 inhibition led us to inhibit both WEE1 and ERK concurrently, which caused further potent growth suppression and enhanced apoptotic death compared with WEE1 inhibition alone. We conclude that system-wide delineation of the KRAS-regulated kinome can identify potential therapeutic targets for KRAS-mutant pancreatic cancer.
AB - Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRASregulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines and then applied multiplexed inhibitor bead/MS to monitor changes in kinase activity and/or expression. We hypothesized that depletion of KRAS would result in downregulation of kinases required for KRAS-mediated transformation and in upregulation of other kinases that could potentially compensate for the deleterious consequences of the loss of KRAS. We identified 15 upregulated and 13 downregulated kinases in common across the panel of cell lines. In agreement with our hypothesis, all 15 of the upregulated kinases have established roles as cancer drivers (e.g., SRC, TGF-β1, ILK), and pharmacological inhibition of one of these upregulated kinases, DDR1, suppressed PDAC growth. Interestingly, 11 of the 13 downregulated kinases have established driver roles in cell cycle progression, particularly in mitosis (e.g., WEE1, Aurora A, PLK1). Consistent with a crucial role for the downregulated kinases in promoting KRAS-driven proliferation, we found that pharmacological inhibition of WEE1 also suppressed PDAC growth. The unexpected paradoxical activation of ERK upon WEE1 inhibition led us to inhibit both WEE1 and ERK concurrently, which caused further potent growth suppression and enhanced apoptotic death compared with WEE1 inhibition alone. We conclude that system-wide delineation of the KRAS-regulated kinome can identify potential therapeutic targets for KRAS-mutant pancreatic cancer.
UR - http://www.scopus.com/inward/record.url?scp=85119896297&partnerID=8YFLogxK
U2 - 10.1016/j.jbc.2021.101335
DO - 10.1016/j.jbc.2021.101335
M3 - Article
C2 - 34688654
AN - SCOPUS:85119896297
SN - 0021-9258
VL - 297
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 5
M1 - 101335
ER -