Ras oncoproteins are mutated in ~30% of all cancers, and the Raf-MEK-ERK kinase cascade is the canonical Ras effector pathway and main clinical targets, with many drugs in development or entering the clinic. However, Ras effector pathway activation is quite heterogeneous among Ras-dependent tumors, as is drug response. Shoc2 (discovered as C. elegans SOC-2 or SUR-8) is the main known regulator of Ras effector usage, since it has been shown to scaffold Ras-Raf signaling. Germline Shoc2 mutations confer phenotypes similar to other Rasopathies, where weak activation of the Ras-Raf pathway confer congenital defects. Thus, Shoc2 regulation may be critical for tumor initiation, progression, maintenance, and treatment.

This study raises the interesting possibility that it is Shoc2 subcellular trafficking in response to EGFR activation that regulates its function. This notion is consistent with evidence in recent years that trafficking Ras itself to different subcellular compartments results in changes in activity and effector selectivity. Why not regulate effector scaffolding similarly? This opens an important area of research: the regulation of Shoc2 may be important for this clinically critical pathway.

The study also raises the interesting possibility that the germline Shoc2 mutation, thought to be a gain of function, may actually be loss of function. This result seems contradictory, since other Rasopathies are caused by weak activation of the Ras-Raf cascade. However, recent insights into the complex regulation of Raf and its scaffold with MEK, Ksr, argue that inhibition of one Raf isoform can result in increased activation of other Raf isoforms.

Many Raf and MEK inhibitors are entering the clinic, yet surprise side-effects and resistance mechanisms are arising. Characterization of novel drug targets and regulatory mechanisms are critical as this pathway is tackled in the clinic.