KRAS functions as a molecular switch, cycling between inactive (GDP-bound) and active (GTP-bound) states to transduce extracellular signals via cell-surface receptors. KRAS signaling occurs through engagement with effector proteins that orchestrate intracellular signaling cascades regulating tumor cell survival and proliferation. Mutations in the KRAS gene occur in approximately one of seven of all human cancers. Up to 90% of pancreatic tumors bear activating KRAS mutations. Direct KRAS blockade has proved challenging, and inhibition of a key downstream effector pathway, the RAF–MEK–ERK cascade, has shown limited success because of activation of feedback networks that keep the pathway in check. SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. BI-3406 is a highly potent, selective, and orally bioavailable SOS1 inhibitor. It binds to the catalytic domain of SOS1, thereby preventing the interaction with KRAS.
BI-3406 binds to SOS1 and thereby blocks protein-protein interaction with RAS-GDP. Moreover, it is the first example of an orally bioavailable SOS1-KRAS interaction inhibitor that reduces RAS-GTP levels and curtails MAPK pathway signaling. It also reduces cell proliferation of a large fraction of KRAS G12C-driven and non-G12C-driven cancers. In addition, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances the sensitivity of KRAS-dependent cancers to MEK inhibition.
In summary, BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, and elucidate its mode of action both in vitro and in vivo. BI-3406 enhances the extent and duration of MAPK pathway inhibition upon the combination with a MEK or KRAS G12C inhibitor. Thus, it is able to counteract adaptive resistance. All in all, this highlights SOS1 inhibition as a promising combination option for MAPK pathway and direct KRAS inhibitors.