H-Ras, K-Ras, and N-Ras regulate cellular growth and survival and are often 
activated by somatic mutation in human tumors. Although oncogenic lesions occur 
in a single Ras isoform within individual tumors, it is unclear whether the 
remaining wild-type isoforms play supporting roles in tumor growth. Here, we 
show that oncogenic and wild-type Ras isoforms play independent and nonredundant 
roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, 
whereas wild-type Ras mediates signaling downstream of activated receptor 
tyrosine kinases (RTK). We show that both are necessary for exponential growth 
of Ras-mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes 
signaling from EGF receptor (EGFR). Depletion of oncogenic Ras with siRNA 
oligonucleotides relieves this negative feedback, leading to the hyperactivation 
of EGFR and wild-type Ras signaling. Consistent with this model, combining 
oncogenic Ras depletion with EGFR inhibition potently increases cell death.
SIGNIFICANCE: The results of this study highlight a novel role for wild-type Ras 
signaling in cancer cells harboring oncogenic RAS mutations. Furthermore, these 
findings reveal that therapeutically targeting oncogenic Ras signaling alone may 
be ineffective owing to feedback activation of RTKs, and suggest that blocking 
upstream RTKs in combination with downstream effector pathways may be beneficial 
in the treatment of Ras-mutant tumors.