Targeting Son of Sevenless 1: The pacemaker of KRAS

Son of Sevenless (SOS) is a guanine nucleotide exchange factor that activates the important cell signaling switch KRAS. SOS acts as a pacemaker for KRAS, the beating heart of cancer, by catalyzing the beating from the KRAS(off) to the KRAS(on) conformation. Activating mutations in SOS1 are common in Noonan syndrome and oncogenic alterations in KRAS drive 1 in seven human cancers. Promising clinical efficacy has been observed for selective KRAS(G12C) inhibitors, but the vast majority of oncogenic KRAS alterations remain undrugged. The discovery of a druggable pocket on SOS1 has led to potent SOS1 inhibitors such as BI-3406. SOS1 inhibition leads to antiproliferative effects against all major KRAS mutants. The first SOS1 inhibitor has entered clinical trials for KRAS-mutated cancers. In this review, we provide an overview of SOS1 function, its association with cancer and RASo-pathies, known SOS1 activators and inhibitors, and a future perspective is provided.

Automated summary

Son of Sevenless (SOS) is a guanine nucleotide exchange factor that plays a key role in activating the important cell signaling switch KRAS. Inhibition of SOS1 with potent inhibitors like BI-3406 has shown promising antiproliferative effects against various oncogenic KRAS mutants. The first SOS1 inhibitor has entered clinical trials for KRAS-mutated cancers, highlighting the potential therapeutic significance of targeting this pathway.