Small Molecule SOS1 Agonists Modulate MAPK and PI3K Signaling via Independent Cellular Responses

Activating mutations in RAS can lead to oncogenesis by enhancing downstream signaling, such as through the MAPK and PI3K pathways. Therefore, therapeutically targeting RAS may perturb multiple signaling pathways simultaneously. One method for modulating RAS signaling is to target the activity of the guanine nucleotide exchange factor SOS1. Our laboratory has discovered compounds that bind to SOS1and activate RAS. Interestingly, these SOS1agonist compounds elicit biphasic modulation of ERK phosphorylation and simultaneous inhibition of AKT phosphorylation levels. Here, we utilized multiple chemically distinct compounds to elucidate whether these effects on MAPK and PI3K signaling by SOS1agonists were mechanistically linked. In addition, we used CRISPR/ Cas9gene-editing to generate clonally derived SOS1knockout cells and identified a potent SOS1agonist that rapidly elicited on-target molecular effects at substantially lower concentrations than those causing off-target effects. Our findings will allow u...