@article{68bc2178f65d41019d73c885a9de6590,
title = "KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS",
abstract = "The mechanism by which the wild-type KRAS allele imparts a growth inhibitory effect to oncogenic KRAS in various cancers, including lung adenocarcinoma (LUAD), is poorly understood. Here, using a genetically inducible model of KRAS loss of heterozygosity (LOH), we show that KRAS dimerization mediates wild-type KRAS-dependent fitness of human and murine KRAS mutant LUAD tumor cells and underlies resistance to MEK inhibition. These effects are abrogated when wild-type KRAS is replaced by KRASD154Q, a mutant that disrupts dimerization at the α4-α5 KRAS dimer interface without changing other fundamental biochemical properties of KRAS, both in vitro and in vivo. Moreover, dimerization has a critical role in the oncogenic activity of mutant KRAS. Our studies provide mechanistic and biological insights into the role of KRAS dimerization and highlight a role for disruption of dimerization as a therapeutic strategy for KRAS mutant cancers. The tumor-suppressive function of wild-type KRAS depends on its dimerization capacity with mutant KRAS.",
keywords = "KRAS oncogene, MAPK pathway, MEK inhibitors, allelic imbalance, dimerization, drug resistance, lung adenocarcinoma, wild-type allele",
author = "Chiara Ambrogio and Jens K{\"o}hler and Zhou, {Zhi Wei} and Haiyun Wang and Raymond Paranal and Jiaqi Li and Marzia Capelletti and Cristina Caffarra and Shuai Li and Qi Lv and Sudershan Gondi and Hunter, {John C.} and Jia Lu and Roberto Chiarle and David Santamar{\'i}a and Westover, {Kenneth D.} and J{\"a}nne, {Pasi A.}",
note = "Funding Information: This work was supported by a Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15 to P.A.J.), the Gadzooks Fund (to P.A.J.), the Cammarata Family Foundation Research Fund (to P.A.J.), the US Department of Defense (W81XWH-16-1-0106 to K.D.W.), the Cancer Prevention and Research Institute of Texas (RP140233 to K.D.W.), the National Natural Science Foundation of China (31571363 and 31771469 to H.W.) and a Mildred-Scheel postdoctoral fellowship from the German Cancer Aid Foundation (70111755 to J.K.). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the scientific partner of SU2C. The authors would like to acknowledge the data from CGP project, which is hosted by the European Bioinformatics Institute under accession number EGAD00001001039. The authors would like to thank Mariano Barbacid and Matthias Drosten for sharing the Ras-less cells, Patricia Nieto for helpful discussion and technical contribution for BRAF/CRAF co-IP experiments, and Eric Smith for generating the graphical abstract. P.A.J. has served as a consultant for and has received sponsored research funding from AstraZeneca. Funding Information: This work was supported by a Stand Up To Cancer-American Cancer Society Lung Cancer Dream Team Translational Research Grant ( SU2C-AACR-DT17-15 to P.A.J.), the Gadzooks Fund (to P.A.J.), the Cammarata Family Foundation Research Fund (to P.A.J.), the US Department of Defense ( W81XWH-16-1-0106 to K.D.W.), the Cancer Prevention and Research Institute of Texas ( RP140233 to K.D.W.), the National Natural Science Foundation of China ( 31571363 and 31771469 to H.W.) and a Mildred-Scheel postdoctoral fellowship from the German Cancer Aid Foundation ( 70111755 to J.K.). Stand Up To Cancer is a program of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research , the scientific partner of SU2C. The authors would like to acknowledge the data from CGP project, which is hosted by the European Bioinformatics Institute under accession number EGAD00001001039. The authors would like to thank Mariano Barbacid and Matthias Drosten for sharing the Ras -less cells, Patricia Nieto for helpful discussion and technical contribution for BRAF/CRAF co-IP experiments, and Eric Smith for generating the graphical abstract. P.A.J. has served as a consultant for and has received sponsored research funding from AstraZeneca. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2018",
month = feb,
day = "8",
doi = "10.1016/j.cell.2017.12.020",
language = "English (US)",
volume = "172",
pages = "857--868.e15",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "4",
}