Combining SOS1 and MEK Inhibitors in a Murine Model of Plexiform Neurofibroma Results in Tumor Shrinkage.

Autor:	Jackson M; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Ahmari N; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Wu J; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Rizvi TA; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Fugate E; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Kim MO; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Dombi E; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Arnhof H; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Boehmelt G; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Düchs MJ; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Long CJ; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Maier U; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Trapani F; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.)., Hofmann MH; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.) nancy.ratner@cchmc.org marco.hofmann@boehringer-ingelheim.com., Ratner N; Division of Experimental Hematology and Cancer Biology, Cancer and Blood Diseases Institute (M.J., N.A., J.W., T.A.R., N.R.) and Department of Radiology (E.F.), Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California (M.-O.K.); Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland (E.D.); Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria (H.A., G.B., F.T., M.H.H.); Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany (M.J.D., C.J.L., U.M.); and Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio (J.W., N.R.) nancy.ratner@cchmc.org marco.hofmann@boehringer-ingelheim.com.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 May; Vol. 385 (2), pp. 106-116. Date of Electronic Publication: 2023 Feb 27.
DOI:	10.1124/jpet.122.001431
Abstrakt:	Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 fl/fl mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibromas are rich in ionized calcium binding adaptor molecule 1 (Iba1)+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEK inhibitor plus SOS1 inhibition in this preclinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas. SIGNIFICANCE STATEMENT: Interfering with the RAS-mitogen-activated protein kinase (RAS-MAPK) cascade upstream of mitogen activated protein kinase kinase (MEK), together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas. (U.S. Government work not protected by U.S. copyright.)
Databáze:	MEDLINE
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