Wild-type KRAS increases survival and resistance to MEK inhibitors in KRAS-mutant lung cancer cells.

  • Major finding: Wild-type KRAS increases survival and resistance to MEK inhibitors in KRAS-mutant lung cancer cells.

  • Concept: Blocking KRAS dimerization suppresses downstream signaling and the growth of KRAS-mutant tumors.

  • Impact: Targeting KRAS dimerization may be a potential therapeutic strategy in patients with KRAS-mutant tumors.


Activating KRAS mutations occur frequently in patients with lung adenocarcinoma and there are currently no effective targeted therapies available to treat patients with KRAS-driven tumors, as targeting downstream MAPK signaling with MEK or ERK inhibitors has not provided a clinical benefit in these patients. KRAS can function as a dimer, suggesting the potential for targeting dimer formation. However, it is not clear if dimerization is required for the oncogenic activity of mutant KRAS or what effect the remaining wild-type KRAS allele has. Ambrogio and colleagues found that loss of wild-type Kras accelerated cell proliferation in KRAS-mutant (KRASG12C, KRASG12D, or KRASG12V) mouse embryonic fibroblasts. In vivo, in a mouse model in which mutant KrasG12V is expressed in lung epithelial cells and the wild-type Kras allele can be conditionally deleted (Kraslox/LSLG12V), mice that retained the wild-type Kras allele exhibited extended survival. Further, expression of the wild-type KRAS protein reduced sensitivity to MEK inhibitors in KRAS mutant cells. A charge-reversal KRASD154Q mutant blocked KRAS dimerization and was sufficient to block the growth-inhibitory effect of wild-type KRAS on mutant KRAS and restore sensitivity to MEK inhibitors, indicating that wild-type KRAS dimerizes with mutant KRAS to produce its growth-inhibitory effects. In vivo, KRASD154Q/G12C tumors with impaired KRAS dimerization grew more slowly than KRASG12C tumors, suggesting that blocking mutant-KRAS dimerization suppresses its oncogenic activity. Indeed, in KRASD154Q/G12C tumors MEK and ERK phosphorylation were reduced, and ERK target genes were downregulated. Taken together, these findings reveal that wild-type KRAS dimerizes with mutant KRAS to impair its oncogenic effects and promote resistance to MEK inhibitors and that mutant KRAS dimerization drives tumorigenesis. These findings suggest the potential for therapeutic targeting of KRAS dimerization in KRAS-mutant tumors.

Ambrogio C, Köhler J, Zhou ZW, Wang H, Paranal R, Li J, et al. KRAS dimerization impacts MEK inhibitor sensitivity and oncogenic activity of mutant KRAS. Cell 2018;172:857–68.e15.

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