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Comment
. 2021 Jan;11(1):17-19.
doi: 10.1158/2159-8290.CD-20-1331.

Suppressing Nucleotide Exchange to Inhibit KRAS-Mutant Tumors

Yulei Zhao  1 , Jenny Y Xue  1   2 , Piro Lito  3   2   4   5
Affiliations
Comment

Suppressing Nucleotide Exchange to Inhibit KRAS-Mutant Tumors

Yulei Zhao et al. Cancer Discov. 2021 Jan.

Abstract

Guanine nucleotide exchange factors (GEF) control the rate-limiting step of physiologic RAS activation. In this issue of Cancer Discovery, Hofmann and colleagues describe the discovery of a selective inhibitor targeting the GEF, SOS1, along with its preclinical effects in suppressing KRAS-mutant tumor growth.See related article by Hofmann et al., p. 142.

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Comment in

  • BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition.
    Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, Sanderson MP, Kessler D, Trapani F, Arnhof H, Rumpel K, Botesteanu DA, Ettmayer P, Gerstberger T, Kofink C, Wunberg T, Zoephel A, Fu SC, Teh JL, Böttcher J, Pototschnig N, Schachinger F, Schipany K, Lieb S, Vellano CP, O'Connell JC, Mendes RL, Moll J, Petronczki M, Heffernan TP, Pearson M, McConnell DB, Kraut N. Hofmann MH, et al. Cancer Discov. 2021 Jan;11(1):142-157. doi: 10.1158/2159-8290.CD-20-0142. Epub 2020 Aug 19. Cancer Discov. 2021. PMID: 32816843 Free PMC article.

Comment on

  • BI-3406, a Potent and Selective SOS1-KRAS Interaction Inhibitor, Is Effective in KRAS-Driven Cancers through Combined MEK Inhibition.
    Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, Sanderson MP, Kessler D, Trapani F, Arnhof H, Rumpel K, Botesteanu DA, Ettmayer P, Gerstberger T, Kofink C, Wunberg T, Zoephel A, Fu SC, Teh JL, Böttcher J, Pototschnig N, Schachinger F, Schipany K, Lieb S, Vellano CP, O'Connell JC, Mendes RL, Moll J, Petronczki M, Heffernan TP, Pearson M, McConnell DB, Kraut N. Hofmann MH, et al. Cancer Discov. 2021 Jan;11(1):142-157. doi: 10.1158/2159-8290.CD-20-0142. Epub 2020 Aug 19. Cancer Discov. 2021. PMID: 32816843 Free PMC article.

References

    1. Boriack-Sjodin PA, Margarit SM, Bar-Sagi D, Kuriyan J. The structural basis of the activation of Ras by Sos. Nature. 1998;394:337–43.
    1. Margarit SM, Sondermann H, Hall BE, Nagar B, Hoelz A, Pirruccello M, et al. Structural evidence for feedback activation by Ras.GTP of the Ras-specific nucleotide exchange factor SOS. Cell. 2003;112:685–95.
    1. Douville E, Downward J. EGF induced SOS phosphorylation in PC12 cells involves P90 RSK-2. Oncogene. 1997;15:373–83.
    1. Lito P, Rosen N, Solit DB. Tumor adaptation and resistance to RAF inhibitors. Nat Med. 2013;19:1401–9.
    1. Patgiri A, Yadav KK, Arora PS, Bar-Sagi D. An orthosteric inhibitor of the Ras-Sos interaction. Nat Chem Biol. 2011;7:585–7.

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