Virtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer

Abstract KRAS is a small GTPase family protein that relays extracellular growth signals to cell nucleus. KRASG12C mutations lead to constitutive proliferation signaling and are prevalent across human cancers. ASP2453 is a novel, highly potent, and selective inhibitor of KRASG12C. Although preclinica...

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Autores principales:	Hiroyuki Sayama, Diana Marcantonio, Takeyuki Nagashima, Masashi Shimazaki, Tsuyoshi Minematsu, Joshua F Apgar, John M. Burke, Lucia Wille, Yasuhisa Nagasaka, Daniel C. Kirouac
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/307d52ab94554a9cbf4a9e35c1594f22
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spelling	oai:doaj.org-article:307d52ab94554a9cbf4a9e35c1594f222021-11-19T15:35:29ZVirtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer2163-830610.1002/psp4.12661https://doaj.org/article/307d52ab94554a9cbf4a9e35c1594f222021-08-01T00:00:00Zhttps://doi.org/10.1002/psp4.12661https://doaj.org/toc/2163-8306Abstract KRAS is a small GTPase family protein that relays extracellular growth signals to cell nucleus. KRASG12C mutations lead to constitutive proliferation signaling and are prevalent across human cancers. ASP2453 is a novel, highly potent, and selective inhibitor of KRASG12C. Although preclinical data suggested impressive efficacy, it remains unclear whether ASP2453 will show more favorable clinical response compared to more advanced competitors, such as AMG 510. Here, we developed a quantitative systems pharmacology (QSP) model linking KRAS signaling to tumor growth in patients with non‐small cell lung cancer. The model was parameterized using in vitro ERK1/2 phosphorylation and in vivo xenograft data for ASP2453. Publicly disclosed clinical data for AMG 510 were used to generate a virtual population, and tumor size changes in response to ASP2453 and AMG 510 were simulated. The QSP model predicted ASP2453 exhibits greater clinical response than AMG 510, supporting potential differentiation and critical thinking for clinical trials.Hiroyuki SayamaDiana MarcantonioTakeyuki NagashimaMasashi ShimazakiTsuyoshi MinematsuJoshua F ApgarJohn M. BurkeLucia WilleYasuhisa NagasakaDaniel C. KirouacWileyarticleTherapeutics. PharmacologyRM1-950ENCPT: Pharmacometrics & Systems Pharmacology, Vol 10, Iss 8, Pp 864-877 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Therapeutics. Pharmacology RM1-950
spellingShingle	Therapeutics. Pharmacology RM1-950 Hiroyuki Sayama Diana Marcantonio Takeyuki Nagashima Masashi Shimazaki Tsuyoshi Minematsu Joshua F Apgar John M. Burke Lucia Wille Yasuhisa Nagasaka Daniel C. Kirouac Virtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer
description	Abstract KRAS is a small GTPase family protein that relays extracellular growth signals to cell nucleus. KRASG12C mutations lead to constitutive proliferation signaling and are prevalent across human cancers. ASP2453 is a novel, highly potent, and selective inhibitor of KRASG12C. Although preclinical data suggested impressive efficacy, it remains unclear whether ASP2453 will show more favorable clinical response compared to more advanced competitors, such as AMG 510. Here, we developed a quantitative systems pharmacology (QSP) model linking KRAS signaling to tumor growth in patients with non‐small cell lung cancer. The model was parameterized using in vitro ERK1/2 phosphorylation and in vivo xenograft data for ASP2453. Publicly disclosed clinical data for AMG 510 were used to generate a virtual population, and tumor size changes in response to ASP2453 and AMG 510 were simulated. The QSP model predicted ASP2453 exhibits greater clinical response than AMG 510, supporting potential differentiation and critical thinking for clinical trials.
format	article
author	Hiroyuki Sayama Diana Marcantonio Takeyuki Nagashima Masashi Shimazaki Tsuyoshi Minematsu Joshua F Apgar John M. Burke Lucia Wille Yasuhisa Nagasaka Daniel C. Kirouac
author_facet	Hiroyuki Sayama Diana Marcantonio Takeyuki Nagashima Masashi Shimazaki Tsuyoshi Minematsu Joshua F Apgar John M. Burke Lucia Wille Yasuhisa Nagasaka Daniel C. Kirouac
author_sort	Hiroyuki Sayama
title	Virtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer
title_short	Virtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer
title_full	Virtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer
title_fullStr	Virtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer
title_full_unstemmed	Virtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer
title_sort	virtual clinical trial simulations for a novel krasg12c inhibitor (asp2453) in non‐small cell lung cancer
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/307d52ab94554a9cbf4a9e35c1594f22
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Virtual clinical trial simulations for a novel KRASG12C inhibitor (ASP2453) in non‐small cell lung cancer

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