| First Author | Ambrogio C | Year | 2018 |
| Journal | Cell | Volume | 172 |
| Issue | 4 | Pages | 857-868.e15 |
| PubMed ID | 29336889 | Mgi Jnum | J:310997 |
| Mgi Id | MGI:6765176 | Doi | 10.1016/j.cell.2017.12.020 |
| Citation | Ambrogio C, et al. (2018) KRAS Dimerization Impacts MEK Inhibitor Sensitivity and Oncogenic Activity of Mutant KRAS. Cell 172(4):857-868.e15 |
| abstractText | 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 KRAS(D154Q), a mutant that disrupts dimerization at the alpha4-alpha5 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. |
