@article{ab921d915de8496299e465d7d25ac120,
title = "Low-Dose Vertical Inhibition of the RAF-MEK-ERK Cascade Causes Apoptotic Death of KRAS Mutant Cancers",
abstract = "We address whether combinations with a pan-RAF inhibitor (RAFi) would be effective in KRAS mutant pancreatic ductal adenocarcinoma (PDAC). Chemical library and CRISPR genetic screens identify combinations causing apoptotic anti-tumor activity. The most potent combination, concurrent inhibition of RAF (RAFi) and ERK (ERKi), is highly synergistic at low doses in cell line, organoid, and rat models of PDAC, whereas each inhibitor alone is only cytostatic. Comprehensive mechanistic signaling studies using reverse phase protein array (RPPA) pathway mapping and RNA sequencing (RNA-seq) show that RAFi/ERKi induced insensitivity to loss of negative feedback and system failures including loss of ERK signaling, FOSL1, and MYC; shutdown of the MYC transcriptome; and induction of mesenchymal-to-epithelial transition. We conclude that low-dose vertical inhibition of the RAF-MEK-ERK cascade is an effective therapeutic strategy for KRAS mutant PDAC.",
keywords = "ERK, FOSL1, KRAS, MYC, RAF, mesenchymal-to-epithelial transition, pancreatic cancer",
author = "Irem Ozkan-Dagliyan and Diehl, {J. Nathaniel} and George, {Samuel D.} and Antje Schaefer and Bjoern Papke and Kathleen Klotz-Noack and Waters, {Andrew M.} and Goodwin, {Craig M.} and Prson Gautam and Mariaelena Pierobon and Sen Peng and Gilbert, {Thomas S.K.} and Lin, {Kevin H.} and Onur Dagliyan and Krister Wennerberg and Petricoin, {Emanuel F.} and Tran, {Nhan L.} and Bhagwat, {Shripad V.} and Tiu, {Ramon V.} and Peng, {Sheng Bin} and Herring, {Laura E.} and Graves, {Lee M.} and Christine Sers and Wood, {Kris C.} and Cox, {Adrienne D.} and Der, {Channing J.}",
note = "Funding Information: We thank Deborah Morrison (National Cancer Institute/NCI) for the RAF shRNA vectors and David Tuveson (Cold Spring Harbor Laboratory) for PDAC organoids. Support was provided by grants from the NCI to A.D.C. and/or C.J.D. from the NCI ( R01CA42978 , R01CA175747 , R01CA223775 , P50CA196510 , U01CA199235 , P01CA203657 , and R35CA232113 ) and from the Pancreatic Cancer Action Network ( 15-90-25-DER ), Department of Defense ( W81XWH-15-1-0611 ), and the Lustgarten Foundation ( 388222 ) to C.J.D. I.O.-D. and J.N.D. were supported by fellowships from the Slomo and Cindy Silvian Foundation . J.N.D. was also supported by NCI T32CA071341 and F30CA243253 . B.P. was supported by the Deutsche Forschungsgemeinschaft ( DFG PA 3051/1-1 ). A.M.W. was supported a fellowship from the American Cancer Society ( PF-18-061 ). C.M.G. was supported by NCI T32CA009156 and F32CA221005 . Funding Information: We thank Deborah Morrison (National Cancer Institute/NCI) for the RAF shRNA vectors and David Tuveson (Cold Spring Harbor Laboratory) for PDAC organoids. Support was provided by grants from the NCI to A.D.C. and/or C.J.D. from the NCI (R01CA42978, R01CA175747, R01CA223775, P50CA196510, U01CA199235, P01CA203657, and R35CA232113) and from the Pancreatic Cancer Action Network (15-90-25-DER), Department of Defense (W81XWH-15-1-0611), and the Lustgarten Foundation (388222) to C.J.D. I.O.-D. and J.N.D. were supported by fellowships from the Slomo and Cindy Silvian Foundation. J.N.D. was also supported by NCI T32CA071341 and F30CA243253. B.P. was supported by the Deutsche Forschungsgemeinschaft (DFG PA 3051/1-1). A.M.W. was supported a fellowship from the American Cancer Society (PF-18-061). C.M.G. was supported by NCI T32CA009156 and F32CA221005. Conceptualization, I.O.-D. and C.J.D.; Methodology, I.O.-D. and C.J.D.; Software, I.O.-D. S.D.G. J.N.D. and O.D.; Validation, I.O.-D. and C.J.D.; Formal Analysis, I.O.-D. S.D.G. J.N.D. and O.D.; Investigation, I.O.-D. S.D.G. A.S. C.M.G. B.P. K.K.-N. A.M.W. P.G. M.P. S.P. T.S.K.G. K.H.L. S.V.B. and R.V.T.; Resources, K.W. E.F.P. N.L.T. S.-B.P. L.M.G. C.S. K.C.W. A.D.C. and C.J.D.; Data Curation, I.O.-D. J.N.D. and C.J.D.; Writing- Original Draft, I.O.-D. A.S. A.D.C. and C.J.D.; Writing- Review & Editing, I.O.-D. A.D.C. and C.J.D.; Visualization, I.O.-D. and C.J.D.; Supervision, C.J.D.; Project Administration, C.J.D.; Funding Acquisition, A.D.C. and C.J.D. C.J.D. is a consultant/advisory board member for Mirati Therapeutics and Deciphera Pharmaceuticals. C.J.D. has received research funding support from Mirati Therapeutics and Deciphera Pharmaceuticals and has consulted for Ribometrix, Jazz Therapeutics, SVB Leerink, Axon Advisors LLC, Third Bridge, SmartAnalyst, 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 of Avant Diagnostics, Inc. and Perthera, Inc. and received funding support from Mirati Therapeutics, Genentech, Inc. and Abbvie, Inc. R.V.T. was previously employed at Eli Lilly and Company and is now employed at Astellas Pharma US. S.V.B. S.-B.P. and R.V.T. are shareholders of Eli Lilly. Publisher Copyright: {\textcopyright} 2020 The Author(s)",
year = "2020",
month = jun,
day = "16",
doi = "10.1016/j.celrep.2020.107764",
language = "English",
volume = "31",
journal = "Cell Reports",
issn = "2211-1247",
number = "11",
}