@article{90e5a9a7ca4a4c9fa126a63594dfec51,
title = "CHK1 protects oncogenic KRAS-expressing cells from DNA damage and is a target for pancreatic cancer treatment",
abstract = "We apply genetic screens to delineate modulators of KRAS mutant pancreatic ductal adenocarcinoma (PDAC) sensitivity to ERK inhibitor treatment, and we identify components of the ATR-CHK1 DNA damage repair (DDR) pathway. Pharmacologic inhibition of CHK1 alone causes apoptotic growth suppression of both PDAC cell lines and organoids, which correlates with loss of MYC expression. CHK1 inhibition also activates ERK and AMPK and increases autophagy, providing a mechanistic basis for increased efficacy of concurrent CHK1 and ERK inhibition and/or autophagy inhibition with chloroquine. To assess how CHK1 inhibition-induced ERK activation promotes PDAC survival, we perform a CRISPR-Cas9 loss-of-function screen targeting direct/indirect ERK substrates and identify RIF1. A key component of non-homologous end joining repair, RIF1 suppression sensitizes PDAC cells to CHK1 inhibition-mediated apoptotic growth suppression. Furthermore, ERK inhibition alone decreases RIF1 expression and phenocopies RIF1 depletion. We conclude that concurrent DDR suppression enhances the efficacy of ERK and/or autophagy inhibitors in KRAS mutant PDAC.",
keywords = "CHK1, DNA damage, ERK, KRAS, MYC, RIF1, pancreatic cancer",
author = "Klomp, {Jennifer E.} and Lee, {Ye S.} and Goodwin, {Craig M.} and Bj{\"o}rn Papke and Klomp, {Jeff A.} and Waters, {Andrew M.} and Stalnecker, {Clint A.} and DeLiberty, {Jonathan M.} and Kristina Drizyte-Miller and Runying Yang and Diehl, {J. Nathaniel} and Yin, {Hongwei H.} and Mariaelena Pierobon and Elisa Baldelli and Ryan, {Meagan B.} and Siqi Li and Jackson Peterson and Smith, {Amber R.} and Neal, {James T.} and McCormick, {Aaron K.} and Kuo, {Calvin J.} and Counter, {Christopher M.} and Petricoin, {Emanuel F.} and Cox, {Adrienne D.} and Bryant, {Kirsten L.} and Der, {Channing J.}",
note = "Funding Information: We thank David Tuveson (Cold Spring Harbor Laboratory) for PDAC organoids. Additionally, we thank Cyrus Vaziri (University of North Carolina at Chapel Hill) for helpful suggestions and critiques. Support was provided by grants to A.D.C. and/or C.J.D. from the National Cancer Institute (NCI) ( R01CA42978 , R01CA175747 , R01CA223775 , P50CA196510 , U01CA199235 , P01CA203657 , and R35CA232113 ) and from the Pancreatic Cancer Action Network / American Association for Cancer Research (AACR) ( 15-90-25-DER ), the U.S. Department of Defense ( W81XWH-15-1-0611 ), and the Lustgarten Foundation ( 388222 ) to C.J.D. K.L.B. was supported by grants from the Pancreatic Cancer Action Network / AACR ( 15-70-25-BRYA ), the NCI ( P50CA196510 and R37CA251877 ), and the Sky Foundation . C.J.K. was supported by grants from the NCI ( U01CA199241 , U01CA21785103 , U54CA224081 , and the Human Cancer Models Initiative). J.E.K. was supported by NCI grants T32CA009156 and F32 CA239328 and the American Cancer Society ( PF-20-069 ). C.A.S. was supported by NCI grants T32CA009156 and F32CA232529 . J.N.D. was supported by the Slomo and Cindy Silvian Foundation and NCI grants T32CA071341 and F30CA243253 . B.P. was supported by Deutsche Forschungsgemeinschaft ( DFG PA 3051/1-1 ). A.M.W. was supported by a fellowship from the American Cancer Society ( PF-18-061 ). C.M.G. was supported by NCI grants T32CA009156 and F32CA221005 . K.D.-M. was supported by NCI grant T32CA009156 . Funding Information: We thank David Tuveson (Cold Spring Harbor Laboratory) for PDAC organoids. Additionally, we thank Cyrus Vaziri (University of North Carolina at Chapel Hill) for helpful suggestions and critiques. Support was provided by grants to A.D.C. and/or C.J.D. from the National Cancer Institute (NCI) (R01CA42978, R01CA175747, R01CA223775, P50CA196510, U01CA199235, P01CA203657, and R35CA232113) and from the Pancreatic Cancer Action Network/American Association for Cancer Research (AACR) (15-90-25-DER), the U.S. Department of Defense (W81XWH-15-1-0611), and the Lustgarten Foundation (388222) to C.J.D. K.L.B. was supported by grants from the Pancreatic Cancer Action Network/AACR (15-70-25-BRYA), the NCI (P50CA196510 and R37CA251877), and the Sky Foundation. C.J.K. was supported by grants from the NCI (U01CA199241, U01CA21785103, U54CA224081, and the Human Cancer Models Initiative). J.E.K. was supported by NCI grants T32CA009156 and F32 CA239328 and the American Cancer Society (PF-20-069). C.A.S. was supported by NCI grants T32CA009156 and F32CA232529. J.N.D. was supported by the Slomo and Cindy Silvian Foundation and NCI grants T32CA071341 and F30CA243253. B.P. was supported by Deutsche Forschungsgemeinschaft (DFG PA 3051/1-1). A.M.W. was supported by a fellowship from the American Cancer Society (PF-18-061). C.M.G. was supported by NCI grants T32CA009156 and F32CA221005. K.D.-M. was supported by NCI grant T32CA009156. Conceptualization, J.E.K. and C.J.D.; Methodology, J.E.K. and C.J.D.; Software, J.E.K. C.M.G. Y.S.L. and J.A.K.; Validation, J.E.K. and C.J.D.; Formal Analysis, J.E.K. C.M.G. Y.S.L. and J.A.K.; Investigation, J.E.K. Y.S.L. C.M.G. B.P. J.A.K. K.L.B. A.M.W. C.A.S. J.M.D. K.D.-M, R.Y. J.N.D. H.H.Y. M.P. S.L. A.R.S. J.T.N. A.K.M. and J.P.; Data Curation, J.E.K. and C.J.D.; Writing ? Original Draft, J.E.K. K.L.B. A.D.C. and C.J.D.; Writing ? Review & Editing, J.E.K. A.D.C. and C.J.D.; Visualization, J.E.K. and C.J.D.; Supervision, C.J.D.; Project Administration, C.J.D.; Funding Acquisition, K.L.B. A.D.C. and C.J.D. 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. receive royalties from Avant Diagnostics. E.F.P. is a consultant to and shareholder in Avant Diagnostics, Inc. and Perthera, Inc. and received funding support from Mirati Therapeutics, Genentech, Inc. and Abbvie, Inc. Publisher Copyright: {\textcopyright} 2021 The Author(s)",
year = "2021",
month = nov,
day = "30",
doi = "10.1016/j.celrep.2021.110060",
language = "English",
volume = "37",
journal = "Cell Reports",
issn = "2211-1247",
number = "9",
}