Assessment of the in vivo activity of PI3K and MEK inhibitors in genetically defined models of colorectal cancer

Raja, Meera, Zverev, Matthew, Seipel, Katja, Williams, Geraint T., Burnett, Alan Kenneth, Clarke, Alan Richard ORCID: https://orcid.org/0000-0002-4281-426X and Shaw, Paul ORCID: https://orcid.org/0000-0002-7467-0619 2015. Assessment of the in vivo activity of PI3K and MEK inhibitors in genetically defined models of colorectal cancer. Molecular Cancer Therapeutics 14 (10) , pp. 2175-2186. 10.1158/1535-7163.MCT-15-0223

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Abstract

The objective of tailoring medicines for cancer patients according to the molecular profile of their disease holds great promise for the improvement of cancer therapy. Nevertheless, this approach has been limited, in part, due to the lack of predictive and informative preclinical studies. Herein, we describe an assessment of the therapeutic potential of targeting PI3K/mTOR and MAPK signaling in genetically defined mouse models of colorectal cancer mirroring disease subtypes targeted for novel therapy in the FOCUS4 trial. Our studies demonstrate that dual PI3K/mTOR inhibition is highly effective in invasive adenocarcinoma models characterized by combinatorial mutations in Apc and Pten; Apc and Kras; and Apc, Pten and Kras. MEK inhibition was effective in the combinatorial Apc and Kras setting, but had no impact in either Apc Pten mutants or in Apc Pten Kras triple mutants. Furthermore, we describe the importance of scheduling for combination studies and show that although no additional benefit is gained in Apc Pten mice, combination of PI3K/mTOR and MAPK inhibition leads to an additive benefit in survival in Apc Kras mice and a synergistic increase in survival in Apc Pten Kras mice. This is the first study using robust colorectal cancer genetically engineered mouse models to support the validity of PI3K/mTOR and MEK inhibitors as tailored therapies for colorectal cancer and highlight the potential importance of drug scheduling in the clinic.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Medicine
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Publisher:	American Association for Cancer Research
ISSN:	1535-7163
Date of Acceptance:	18 July 2015
Last Modified:	15 Dec 2023 07:18
URI:	https://orca.cardiff.ac.uk/id/eprint/73175

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