Abstract
The RAS family of oncogenes (HRAS, NRAS, and KRAS) are among the most frequently mutated protein families in cancers. RAS-mutated tumors were originally thought to proliferate independently of upstream signaling inputs, but we now know that non-mutated wild-type (WT) RAS proteins play an important role in modulating downstream effector signaling and driving therapeutic resistance in RAS-mutated cancers. This modulation is complex as different WT RAS family members have opposing functions. The protein product of the WT RAS allele of the same isoform as mutated RAS is often tumor-suppressive and lost during tumor progression. In contrast, RTK-dependent activation of the WT RAS proteins from the two non-mutated WT RAS family members is tumor-promoting. Further, rebound activation of RTK–WT RAS signaling underlies therapeutic resistance to targeted therapeutics in RAS-mutated cancers. The contributions of WT RAS to proliferation and transformation in RAS-mutated cancer cells places renewed interest in upstream signaling molecules, including the phosphatase/adaptor SHP2 and the RasGEFs SOS1 and SOS2, as potential therapeutic targets in RAS-mutated cancers.
Highlights
The RTK/RAS pathway (Figure 1A) is among the most commonly mutated pathways in cancer [1,2]
In contrast to Dependency Map Portal (DepMap) data, which analyzed individual gene knockdowns, the siREN screen knocked down all genes of genetic ‘nodes’ simultaneously; the WT RAS node knocked down both HRAS and NRAS
We further showed that there was a hierarchical requirement for SOS2 to drive mutant RAS-dependent transformation, with KRAS > NRAS > HRAS
Summary
The RTK/RAS pathway (Figure 1A) is among the most commonly mutated pathways in cancer [1,2]. Understanding the signaling context of mutant RAS is key to developing indirect targeting and combination therapy strategies to better manage these cancers. While typical models of oncogene activation assume that the mutated protein drives oncogenesis separately from the wild-type family members, the evidence that non-mutant wild-type (WT) RAS proteins influence cancer initiation and growth in RAS-mutated cancers is well-established and several mechanisms for the effects have been proposed. HRAS- and KRAS-mutated cells.ofIn HRASRAF/MEK/ERK versus PI3K/AKT signaling in HRAS- and KRAS-mutated cancer cells. In HRASmutated cells, mutant HRAS activates PI3K/AKT signaling, whereas RTK-WT N/KRAS activate RAF/MEK/ERK signaling. Mutated cells, mutant HRAS activates PI3K/AKT signaling, whereas RTK-WT N/KRAS activate.
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