| Reference | [1]. Cancer Discov. 2021 Jan;11(1):142-157. doi: 10.1158/2159-8290.CD-20-0142. Epub 2020 Aug 19.<br />
BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition.<br />
Hofmann MH(#)(1), Gmachl M(#)(2), Ramharter J(#)(2), Savarese F(2), Gerlach D(2), Marszalek JR(3), Sanderson MP(2), Kessler D(2), Trapani F(2), Arnhof H(2), Rumpel K(2), Botesteanu DA(2), Ettmayer P(2), Gerstberger T(2), Kofink C(2), Wunberg T(2), Zoephel A(2), Fu SC(4), Teh JL(3), Böttcher J(2), Pototschnig N(2), Schachinger F(2), Schipany K(2), Lieb S(2), Vellano CP(3), O'Connell JC(5), Mendes RL(5), Moll J(2), Petronczki M(2), Heffernan TP(3), Pearson M(2), McConnell DB(2), Kraut N(1).<br />
Author information: (1)Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. [email protected] [email protected]. (2)Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. (3)TRACTION Platform, Division of Therapeutics Discovery, The University of Texas MD Anderson Cancer Center, Houston, Texas. (4)Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. (5)Forma Therapeutics, Watertown, Massachusetts. (#)Contributed equally<br />
Comment in Cancer Discov. 2021 Jan;11(1):17-19.<br />
Comment on Cancer Discov. 2021 Jan;11(1):17-19.<br />
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.<br />
DOI: 10.1158/2159-8290.CD-20-0142 PMCID: PMC7892644 PMID: 32816843 [Indexed for MEDLINE]<br />
<br />
[2]. J Thorac Oncol. 2021 May 7:S1556-0864(21)02132-8. doi: 10.1016/j.jtho.2021.04.015. Online ahead of print.<br />
KRAS Secondary Mutations That Confer Acquired Resistance to KRAS G12C Inhibitors, Sotorasib and Adagrasib, and Overcoming Strategies: Insights From the In Vitro Experiments.<br />
Koga T(1), Suda K(1), Fujino T(1), Ohara S(1), Hamada A(1), Nishino M(1), Chiba M(1), Shimoji M(1), Takemoto T(1), Arita T(2), Gmachl M(3), Hofmann MH(3), Soh J(1), Mitsudomi T(4).<br />
Author information: (1)Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. (2)Specialty Care Medicine, Medicine Division, Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan. (3)Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. (4)Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan. Electronic address: [email protected].<br />
INTRODUCTION: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance. METHODS: We chronically exposed Ba/F3 cells transduced with KRASG12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated. RESULTS: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib. CONCLUSIONS: We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.<br />
DOI: 10.1016/j.jtho.2021.04.015 PMID: 33971321<br />
<br />
[3]. J Med Chem. 2021 May 27;64(10):6569-6580. doi: 10.1021/acs.jmedchem.0c01949. Epub 2021 Mar 15.<br />
One Atom Makes All the Difference: Getting a Foot in the Door between SOS1 and KRAS.<br />
Ramharter J(1), Kessler D(1), Ettmayer P(1), Hofmann MH(1), Gerstberger T(1), Gmachl M(1), Wunberg T(1), Kofink C(1), Sanderson M(1), Arnhof H(1), Bader G(1), Rumpel K(1), Zöphel A(1), Schnitzer R(1), Böttcher J(1), O'Connell JC(2), Mendes RL(2), Richard D(2), Pototschnig N(1), Weiner I(1), Hela W(1), Hauer K(1), Haering D(1), Lamarre L(1), Wolkerstorfer B(1), Salamon C(1), Werni P(1), Munico-Martinez S(1), Meyer R(1), Kennedy MD(1), Kraut N(1), McConnell DB(1).<br />
Author information: (1)Boehringer Ingelheim RCV GmbH & Co KG, Dr. Boehringer-Gasse 5-11, A-1121 Vienna, Austria. (2)Forma Therapeutics, 500 Arsenal Street, Suite 100, Watertown, Massachusetts 02472, United States.<br />
KRAS, the most common oncogenic driver in human cancers, is controlled and signals primarily through protein-protein interactions (PPIs). The interaction between KRAS and SOS1, crucial for the activation of KRAS, is a typical, challenging PPI with a large contact surface area and high affinity. Here, we report that the addition of only one atom placed between Y884SOS1 and A73KRAS is sufficient to convert SOS1 activators into SOS1 inhibitors. We also disclose the discovery of BI-3406. Combination with the upstream EGFR inhibitor afatinib shows in vivo efficacy against KRASG13D mutant colorectal tumor cells, demonstrating the utility of BI-3406 to probe SOS1 biology. These findings challenge the dogma that large molecules are required to disrupt challenging PPIs. Instead, a "foot in the door" approach, whereby single atoms or small functional groups placed between key PPI interactions, can lead to potent inhibitors even for challenging PPIs such as SOS1-KRAS.<br />
DOI: 10.1021/acs.jmedchem.0c01949 PMID: 33719426 [Indexed for MEDLINE]<br />
<br />
[4]. J Med Chem. 2021 May 27;64(10):6566-6568. doi: 10.1021/acs.jmedchem.1c00698. Epub 2021 May 7.<br />
Breaking Oncogene Addiction: Getting RTK/RAS-Mutated Cancers off the SOS.<br />
Sheffels E(1), Kortum RL(1).<br />
Author information: (1)Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, United States.<br />
In RTK/RAS-mutated cancers, therapeutic resistance is driven by rebound activation of multiple RTKs; broad inhibition of RTK signaling can potentially delay therapeutic resistance for a majority of patients. A new SOS1 inhibitor, BI-3406, broadly inhibits proximal RTK signaling will greatly expand the efficacy of therapies used to treat RTK/RAS-mutated cancers.<br />
DOI: 10.1021/acs.jmedchem.1c00698 PMID: 33961431 [Indexed for MEDLINE]<br />
<br />
[5]. Curr Opin Chem Biol. 2021 Jun;62:109-118. doi: 10.1016/j.cbpa.2021.02.014. Epub 2021 Apr 10.<br />
Targeting Son of Sevenless 1: The pacemaker of KRAS.<br />
Kessler D(1), Gerlach D(1), Kraut N(1), McConnell DB(2).<br />
Author information: (1)Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120, Vienna, Austria. (2)Discovery Research, Boehringer Ingelheim Regional Center Vienna GmbH & Co KG, 1120, Vienna, Austria. Electronic address: [email protected].<br />
Son of Sevenless (SOS) is a guanine nucleotide exchange factor that activates the important cell signaling switch KRAS. SOS acts as a pacemaker for KRAS, the beating heart of cancer, by catalyzing the "beating" from the KRAS(off) to the KRAS(on) conformation. Activating mutations in SOS1 are common in Noonan syndrome and oncogenic alterations in KRAS drive 1 in seven human cancers. Promising clinical efficacy has been observed for selective KRASG12C inhibitors, but the vast majority of oncogenic KRAS alterations remain undrugged. The discovery of a druggable pocket on SOS1 has led to potent SOS1 inhibitors such as BI-3406. SOS1 inhibition leads to antiproliferative effects against all major KRAS mutants. The first SOS1 inhibitor has entered clinical trials for KRAS-mutated cancers. In this review, we provide an overview of SOS1 function, its association with cancer and RASopathies, known SOS1 activators and inhibitors, and a future perspective is provided.<br />
DOI: 10.1016/j.cbpa.2021.02.014 PMID: 33848766
|
