2. Academic Validation
  3. Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS-mutant cancers

Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS-mutant cancers

  • Proc Natl Acad Sci U S A. 2024 Feb 27;121(9):e2319492121. doi: 10.1073/pnas.2319492121.
Robin A Jansen 1,  Sara Mainardi 1,  Matheus Henrique Dias 1,  Astrid Bosma 1,  Emma van Dijk 1,  Roland Selig 2,  Wolfgang Albrecht 2,  Stefan A Laufer 3 4 5,  Lars Zender 4 5 6 7,  René Bernards 1
Affiliations

Affiliations

  • 1 Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
  • 2 HepaRegeniX GmbH, Tuebingen 72072, Germany.
  • 3 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Tübingen 72074, Germany.
  • 4 Tübingen Center for Academic Drug Discovery and Development, Tübingen 72074, Germany.
  • 5 Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies" (EXC 2180), Eberhard Karls Universität Tübingen, Tübingen 72076, Germany.
  • 6 Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen 72076, Germany.
  • 7 German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
PMID: 38377196 DOI: 10.1073/pnas.2319492121
Abstract

The Kirsten rat sarcoma viral oncogene homologue KRAS is among the most commonly mutated oncogenes in human cancers, thus representing an attractive target for precision oncology. The approval for clinical use of the first selective inhibitors of G12C mutant KRAS therefore holds great promise for Cancer treatment. However, despite initial encouraging clinical results, the overall survival benefit that patients experience following treatment with these inhibitors has been disappointing to date, pointing toward the need to develop more powerful combination therapies. Here, we show that responsiveness to KRASG12C and pan-RAS inhibitors in KRAS-mutant lung and colon Cancer cells is limited by feedback activation of the parallel MAP2K4-JNK-JUN pathway. Activation of this pathway leads to elevated expression of Receptor Tyrosine Kinases that reactivate KRAS and its downstream effectors in the presence of drug. We find that the combination of sotorasib, a drug targeting KRASG12C, and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRASG12C-mutant lung and colon Cancer cells. Moreover, combining HRX-0233 and sotorasib is well-tolerated and resulted in durable tumor shrinkage in mouse xenografts of human lung Cancer cells, suggesting a therapeutic strategy for KRAS-driven cancers.

Keywords

KRAS; drug resistance; signal transduction.

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