Small-molecule inhibition of MAP2K4 is synergistic with RAS inhibitors in KRAS -mutant cancers.
| Autor: | Jansen RA; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands., Mainardi S; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands., Dias MH; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands., Bosma A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands., van Dijk E; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands., Selig R; HepaRegeniX GmbH, Tuebingen 72072, Germany., Albrecht W; HepaRegeniX GmbH, Tuebingen 72072, Germany., Laufer SA; Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität Tübingen, Tübingen 72074, Germany.; Tübingen Center for Academic Drug Discovery and Development, Tübingen 72074, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies' (EXC 2180), Eberhard Karls Universität Tübingen, Tübingen 72076, Germany., Zender L; Tübingen Center for Academic Drug Discovery and Development, Tübingen 72074, Germany.; Cluster of Excellence iFIT (EXC 2180) 'Image-Guided and Functionally Instructed Tumor Therapies' (EXC 2180), Eberhard Karls Universität Tübingen, Tübingen 72076, Germany.; Department of Medical Oncology and Pneumology, University Hospital Tübingen, Tübingen 72076, Germany.; German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany., Bernards R; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands. |
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| Jazyk: | angličtina |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Feb 27; Vol. 121 (9), pp. e2319492121. Date of Electronic Publication: 2024 Feb 20. |
| DOI: | 10.1073/pnas.2319492121 |
| Abstrakt: | 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 KRAS G12C 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 KRAS G12C , and the MAP2K4 inhibitor HRX-0233 prevents this feedback activation and is highly synergistic in a panel of KRAS G12C -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. Competing Interests: Competing interests statement:W.A. and R.S. are employees of HepaRegeniX. W.A. and L.Z. are shareholders of HepaRegeniX. R.B. received research funding from HepaRegeniX. R.S., W.A., and S.A.L. are listed as inventors of the small molecule MAP2K4 inhibitor used here. |
| Databáze: | MEDLINE |
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