BI-3406, a Potent and Selective SOS1–KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition

Abstract

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 GTPloaded 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. SignificanceTo date, there are no effective targeted pan-KRAS therapies. In-depth characterization of BI-3406 activity and identification of MEK inhibitors as effective combination partners provide an attractive therapeutic concept for the majority of KRAS mutant cancers, including those fueled by the most prevalent mutant KRAS oncoproteins G12D, G12V, G12C and G13D.Research.

Targeting KRAS: The Elephant in the Room of Epithelial Cancers

“…These observations suggest that inhibition at both levels represents a good strategy to efficiently block KRAS pathway and prevent escape. The combination treatment of SOS1 with MEK inhibitor achieved good results in vitro and in vivo murine models, with robust pathway inhibition and tumor regression ( 18 ). Based on these preliminary preclinical results, BI 1701963, the second representative of SOS1 inhibitors, is being tested, alone and in combination with MEK inhibitor trametinib, in a phase I clinical trial in cancer patients carrying pan-KRAS mutations (NCT04111458).…”

Histone demethylase KDM5A promotes tumorigenesis of osteosarcoma tumor

“…Next, GO analysis and GSEA of KDM5A-KO-related transcriptome indicated that KDM5A activates multiple signaling pathways, including EMT, IL6/JAK/STAT3, and TNF-α/NF-κB to promote proliferation. These pathways have been reported to play an important role in the osteosarcoma progression [24][25][26][27] . As the gene involved in the largest number signaling, interleukin-6 (IL6) as a multifunctional cytokine, promoted glycolytic metabolism and significantly increased proliferation, colony formation of, and promoting an EMT-like phenotype of osteosarcoma cells 25 .…”

“…S3). Among the enrichment sets, some networks were commonly related to proliferation of osteosarcoma, such as epithelial-mesenchymal transition (EMT) 24 , IL6/JAK/ STAT3 25 , KARS 26 , and TNF-α/NF-κB pathway 27 . Among these sets (Table S1), there were 12 genes that are involved in >4 pathways, including IL6 (shared by eight pathways), TNFAIP3 (shared by six pathways), IL15 and INHBA (shared by five pathways), and CCL2, ICMA1, IL1B, IL7, IRF7, ITGB3, LIF, and MMP14 (shared by four pathways) (Fig.…”

Targeting KRAS in Cancer: Promising Therapeutic Strategies

“…One study unveiled that a novel competitive ATP inhibitor targeting ERK1 and ERK2 may have clinical benefit in KRAS mutant AML cases [14]. Inhibition of the KRAS activator SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1) is an effective approach when treating cancers driven by KRAS [15]. In addition, inhibiting SOS1 increases the sensitivity of KRAS mutant cancers to MEK inhibition.…”