Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic Nras^G12D in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased Nras^G12D gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of Nras^G12D/G12D hematopoietic cells. Modulating Nras^G12D dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MAP-ERK kinase (MEK) inhibition. Furthermore, enforced WT N-Ras expression neither suppressed the growth of Nras-mutant cells nor inhibited myeloid transformation by exogenous Nras^G12D. Importantly, NRAS expression increased in human cancer cell lines with NRAS mutations. These data have therapeutic implications and support reconsidering the proposed tumor suppressor activity of WT Ras in other cancers.

Significance: Understanding the mechanisms of Ras-induced transformation and adaptive cellular responses is fundamental. The observation that oncogenic Nras lacks tumor suppressor activity, whereas increased dosage strongly modulates cell growth and alters sensitivity to MEK inhibition, suggests new therapeutic opportunities in cancer. Cancer Discov; 3(9); 993–1001. ©2013 AACR.

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