Extensive preclinical validation of combined RMC-4550 and LY3214996 supports clinical investigation for KRAS mutant pancreatic cancer.

Autor:	Frank KJ; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Mulero-Sánchez A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands., Berninger A; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Ruiz-Cañas L; Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (IIBM), CSIC-UAM, 28029 Madrid, Spain; Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain., Bosma A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands., Görgülü K; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Wu N; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Diakopoulos KN; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Kaya-Aksoy E; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Ruess DA; Department of General and Visceral Surgery, Center of Surgery, Medical Center-University of Freiburg, 79106 Freiburg, Germany., Kabacaoğlu D; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Schmidt F; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Kohlmann L; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., van Tellingen O; Division of Pharmacology, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands., Thijssen B; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands., van de Ven M; Mouse Clinic for Cancer and Aging Research, Preclinical Intervention Unit, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands., Proost N; Mouse Clinic for Cancer and Aging Research, Preclinical Intervention Unit, The Netherlands Cancer Institute, 1066CX Amsterdam, the Netherlands., Kossatz S; Department of Nuclear Medicine at Klinikum Rechts der Isar and Central Institute for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany; Department of Chemistry, Technische Universität München, 85748 Munich, Germany., Weber WA; Department of Nuclear Medicine at Klinikum Rechts der Isar and Central Institute for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany., Sainz B Jr; Department of Biochemistry, Universidad Autónoma de Madrid (UAM) and Instituto de Investigaciones Biomédicas 'Alberto Sols' (IIBM), CSIC-UAM, 28029 Madrid, Spain; Chronic Diseases and Cancer, Area 3, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), 28034 Madrid, Spain., Bernards R; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands., Algül H; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Lesina M; Comprehensive Cancer Center Munich at Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany., Mainardi S; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, the Netherlands. Electronic address: s.mainardi@nki.nl.
Jazyk:	angličtina
Zdroj:	Cell reports. Medicine [Cell Rep Med] 2022 Nov 15; Vol. 3 (11), pp. 100815.
DOI:	10.1016/j.xcrm.2022.100815
Abstrakt:	Over 90% of pancreatic cancers present mutations in KRAS, one of the most common oncogenic drivers overall. Currently, most KRAS mutant isoforms cannot be targeted directly. Moreover, targeting single RAS downstream effectors induces adaptive resistance mechanisms. We report here on the combined inhibition of SHP2, upstream of KRAS, using the allosteric inhibitor RMC-4550 and of ERK, downstream of KRAS, using LY3214996. This combination shows synergistic anti-cancer activity in vitro, superior disruption of the MAPK pathway, and increased apoptosis induction compared with single-agent treatments. In vivo, we demonstrate good tolerability and efficacy of the combination, with significant tumor regression in multiple pancreatic ductal adenocarcinoma (PDAC) mouse models. Finally, we show evidence that 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu