2. Academic Validation
  3. Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance

Co-targeting SOS1 enhances the antitumor effects of KRASG12C inhibitors by addressing intrinsic and acquired resistance

  • Nat Cancer. 2024 Aug 5. doi: 10.1038/s43018-024-00800-6.
Venu Thatikonda # 1 2,  Hengyu Lyu # 3,  Sabine Jurado 4,  Kaja Kostyrko 4,  Christopher A Bristow 3,  Christoph Albrecht 4,  Donat Alpar 4,  Heribert Arnhof 4,  Oliver Bergner 4,  Karin Bosch 4,  Ningping Feng 3,  Sisi Gao 3,  Daniel Gerlach 4,  Michael Gmachl 4,  Melanie Hinkel 4,  Simone Lieb 4,  Astrid Jeschko 4,  Annette A Machado 3,  Thomas Madensky 4,  Ethan D Marszalek 3,  Mikhila Mahendra 3,  Gabriella Melo-Zainzinger 4,  Jessica M Molkentine 3,  Philipp A Jaeger 4,  David H Peng 3,  Robyn L Schenk 4,  Alexey Sorokin 5,  Sandra Strauss 4,  Francesca Trapani 4,  Scott Kopetz 5,  Christopher P Vellano 3,  Mark Petronczki 4,  Norbert Kraut 4,  Timothy P Heffernan 3,  Joseph R Marszalek 3,  Mark Pearson 4,  Irene C Waizenegger 4,  Marco H Hofmann 6
Affiliations

Affiliations

  • 1 Boehringer Ingelheim RCV, Vienna, Austria. vthatikonda@exscientia.co.uk.
  • 2 Exscientia, Vienna, Austria. vthatikonda@exscientia.co.uk.
  • 3 Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 4 Boehringer Ingelheim RCV, Vienna, Austria.
  • 5 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
  • 6 Boehringer Ingelheim RCV, Vienna, Austria. marco.hofmann@boehringer-ingelheim.com.
  • # Contributed equally.
PMID: 39103541 DOI: 10.1038/s43018-024-00800-6
Abstract

Combination approaches are needed to strengthen and extend the clinical response to KRASG12C inhibitors (KRASG12Ci). Here, we assessed the antitumor responses of KRASG12C mutant lung and colorectal Cancer Models to combination treatment with a SOS1 inhibitor (SOS1i), BI-3406, plus the KRASG12C inhibitor, adagrasib. We found that responses to BI-3406 plus adagrasib were stronger than to adagrasib alone, comparable to adagrasib with SHP2 (SHP2i) or EGFR inhibitors and correlated with stronger suppression of RAS-MAPK signaling. BI-3406 plus adagrasib treatment also delayed the emergence of acquired resistance and elicited antitumor responses from adagrasib-resistant models. Resistance to KRASG12Ci seemed to be driven by upregulation of MRAS activity, which both SOS1i and SHP2i were found to potently inhibit. Knockdown of SHOC2, a MRAS complex partner, partially restored response to KRASG12Ci treatment. These results suggest KRASG12C plus SOS1i to be a promising strategy for treating both KRASG12Ci naive and relapsed KRASG12C-mutant tumors.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130149
    99.93%, KRAS G12C Inhibitor
    Ras