3 years ago

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS

KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS
Jia Lu, Zhi-Wei Zhou, Qi Lv, Marzia Capelletti, Raymond Paranal, David Santamaría, Jiaqi Li, Cristina Caffarra, Sudershan Gondi, Shuai Li, Pasi A. Jänne, Roberto Chiarle, John C. Hunter, Haiyun Wang, Jens Köhler, Kenneth D. Westover, Chiara Ambrogio

Summary

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.

Publisher URL: http://www.cell.com/cell/fulltext/S0092-8674(17)31500-3

DOI: 10.1016/j.cell.2017.12.020

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