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

Abstract

<div>Abstract<p><i>KRAS</i> is the most frequently mutated driver of pancreatic, colorectal, and non–small cell lung cancers. 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. 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.</p>Significance:<p>To 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.</p><p><i>See related commentary by Zhao et al., p. 17</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1</i></p></div>

Discovery of a Potent Dual Son of Sevenless 1 (SOS1) and Epidermal Growth Factor Receptor (EGFR) Inhibitor for the Treatment of Prostate Cancer

“…16,17 Son of sevenless 1 (SOS1), which acts as a pivotal guanine exchange factor (GEF) capable of binding to KRAS and activating the transition from KRAS-GDP (inactive form) to KRAS-GTP (active form), is a central node of RAS-related signaling pathways. 18,19 SOS1 deletion would inactivate RAS protein and inhibit the phosphorylation of its downstream effectors, such as ERK and AKT, resulting in decreased survival, proliferation, and migration of tumor cells. 18,20−22 Recently, the development of SOS1-targeting binders is considered a more prospective strategy for the suppression of abnormal RAS signaling as opposed to direct inhibition of the "undruggable" KRAS protein, due to a clear binding pocket located near the SOS1:KRAS interface at the SOS1 catalytic site.…”

“…29 BI-3406 sharing the same quinazoline scaffold as BAY-293 exhibited potent antiproliferative effects on most wild-type and G12C-driven cancer cells, and its subsequent modification led to the identification of BI 1701963, which became the first SOS1 inhibitor to enter clinical trials. 18,30 However, two clinical trials of BI 1701963 (NCT04835714, NCT04627142) have been declared terminated because of unexpected toxicity findings. 31 So far, there are no available inhibitors targeting SOS1 on the market.…”