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
  • 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.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-130149
    Adagrasib
    99.96%, KRAS G12C Inhibitor
    target: Ras
    Research Areas: Cancer