GSE128385
BI-3406, a potent and selective SOS1::KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition
KRAS is the most frequently mutated driver of pancreatic, colorectal, and non-small cell lung cancers. Direct KRAS blockade has proven challenging and inhibition of a key downstream effector pathway, the RAF-MEK-ERK cascade, has shown limited success due to activation of feedback networks that keep the pathway in check. We hypothesized that inhibiting SOS1, a KRAS activator and important feedback node, represents an effective approach to treat KRAS-driven cancers. We report the discovery of a highly potent, selective and orally bioavailable small-molecule SOS1 inhibitor, BI-3406, that binds to the catalytic domain of SOS1 thereby preventing the interaction with KRAS. BI-3406 reduces formation of GTP-loaded RAS and limits cellular proliferation of a broad range of KRAS-driven cancers. Importantly, BI-3406 attenuates feedback reactivation induced by MEK inhibitors and thereby enhances sensitivity of KRAS-dependent cancers to MEK inhibition. Combined SOS1 and MEK inhibition represents a novel and effective therapeutic concept to address KRAS-driven tumors. Overall design: In-vivo biomarker experiments were conducted using MIA PaCa-2 in a cell line derived xenograft experiment. Groups included an untreated control group at T=0, Natrosol treated control groups, as well as BI-3406 compound treated groups. A daily b.i.d dosing treatment schema was used, with a delta of 6h between treatments. Tumor material was extracted at 4h, 10h, 24h post-first treatment, followed by RNA isolation. Samples were then subjected to QuantSeq 3' mRNA sequencing for RNA quantification. All groups comprised 5-6 animals, however some samples were excluded from the analysis due to low quality of input RNA and sequencing.