<p class="first" id="d3132386e348">KRAS 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. SIGNIFICANCE: 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.See related commentary by Zhao et al., p. 17.This article is highlighted in the
In This Issue feature, p. 1.
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