2. Academic Validation
  3. Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

Combined KRASG12C and SOS1 inhibition enhances and extends the anti-tumor response in KRASG12C-driven cancers by addressing intrinsic and acquired resistance

  • bioRxiv. 2023 Jan 23:2023.01.23.525210. doi: 10.1101/2023.01.23.525210.
Venu Thatikonda 1,  Hengyu Lu 2,  Sabine Jurado 1,  Kaja Kostyrko 1,  Christopher A Bristow 2,  Karin Bosch 1,  Ningping Feng 2,  Sisi Gao 2,  Daniel Gerlach 1,  Michael Gmachl 1,  Simone Lieb 1,  Astrid Jeschko 1,  Annette A Machado 2,  Ethan D Marszalek 2,  Mikhila Mahendra 2,  Philipp A Jaeger 1,  Alexey Sorokin 3,  Sandra Strauss 1,  Francesca Trapani 1,  Scott Kopetz 3,  Christopher P Vellano 2,  Mark Petronczki 1,  Norbert Kraut 1,  Timothy P Heffernan 2,  Joseph R Marszalek 2,  Mark Pearson 1,  Irene Waizenegger 1,  Marco H Hofmann 1
Affiliations

Affiliations

  • 1 Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria.
  • 2 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.
  • 3 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
PMID: 36747713 DOI: 10.1101/2023.01.23.525210
Abstract

Efforts to improve the anti-tumor response to KRASG12C targeted therapy have benefited from leveraging combination approaches. Here, we compare the anti-tumor response induced by the SOS1-KRAS interaction inhibitor, BI-3406, combined with a KRASG12C inhibitor (KRASG12Ci) to those induced by KRASG12Ci alone or combined with SHP2 or EGFR inhibitors. In lung Cancer and colorectal Cancer (CRC) models, BI-3406 plus KRASG12Ci induces an anti-tumor response stronger than that observed with KRASG12Ci alone and comparable to those by the Other combinations. This enhanced anti-tumor response is associated with a stronger and extended suppression of RAS-MAPK signaling. Importantly, BI-3406 plus KRASG12Ci treatment delays the emergence of acquired adagrasib resistance in both CRC and lung Cancer models and is associated with re-establishment of anti-proliferative activity in KRASG12Ci-resistant CRC models. Our findings position KRASG12C plus SOS1 inhibition therapy as a promising strategy for treating both KRASG12C-mutated tumors as well as for addressing acquired resistance to KRASG12Ci.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130149
    99.96%, KRAS G12C Inhibitor
    Ras