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Hofmann, Marco H.; Gmachl, Michael; Ramharter, Juergen; Savarese, Fabio; Gerlach, Daniel; Marszalek, Joseph R.; Sanderson, Michael P.; Kessler, Dirk; Trapani, Francesca; Arnhof, Heribert; Rumpel, Klaus; Botesteanu, Dana-Adriana; Ettmayer, Peter; Gerstberger, Thomas; Kofink, Christiane; Wunberg, Tobias; Zoephel, Andreas; Fu, Szu-Chin; Teh, Jessica L.; Böttcher, Jark; Pototschnig, Nikolai; Schachinger, Franziska; Schipany, Katharina; Lieb, Simone; [...]

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

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  • Medientyp: E-Artikel
  • Titel: BI-3406, a Potent and Selective SOS1–KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition
  • Beteiligte: Hofmann, Marco H.; Gmachl, Michael; Ramharter, Juergen; Savarese, Fabio; Gerlach, Daniel; Marszalek, Joseph R.; Sanderson, Michael P.; Kessler, Dirk; Trapani, Francesca; Arnhof, Heribert; Rumpel, Klaus; Botesteanu, Dana-Adriana; Ettmayer, Peter; Gerstberger, Thomas; Kofink, Christiane; Wunberg, Tobias; Zoephel, Andreas; Fu, Szu-Chin; Teh, Jessica L.; Böttcher, Jark; Pototschnig, Nikolai; Schachinger, Franziska; Schipany, Katharina; Lieb, Simone; [...]
  • Erschienen: American Association for Cancer Research (AACR), 2021
  • Erschienen in: Cancer Discovery
  • Sprache: Englisch
  • DOI: 10.1158/2159-8290.cd-20-0142
  • ISSN: 2159-8274; 2159-8290
  • Schlagwörter: Oncology
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title /> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Significance:</jats:title> <jats: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.</jats:p> <jats:p>See related commentary by Zhao et al., p. 17.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 1</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang