Reference Detail

Ref Type Journal Article
PMID (26206338)
Authors Raja M, Zverev M, Seipel K, Williams GT, Clarke AR, Shaw PH
Title Assessment of the In Vivo Activity of PI3K and MEK Inhibitors in Genetically Defined Models of Colorectal Cancer.
Journal Molecular cancer therapeutics
Vol 14
Issue 10
Date 2015 Oct
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
APC inact mut KRAS G12D colorectal cancer sensitive BEZ235 Preclinical Actionable In a preclinical study, BEZ235 inhibited PI3K/mTOR signaling in tumors and increased survival in transgenic animal models of colorectal cancer driven by APC inactivation and KRAS G12D (PMID: 26206338). 26206338
APC inact mut KRAS G12D colorectal cancer sensitive Binimetinib Preclinical Actionable In a preclinical study, Binimetinib (MEK162) increased apoptosis in tumors and improved survival in transgenic animal models of colorectal cancer driven by APC inactivation and KRAS G12D (PMID: 26206338). 26206338
APC inact mut KRAS G12D PTEN inact mut colorectal cancer no benefit Binimetinib Preclinical Actionable In a preclinical study, Binimetinib (MEK162) increased both apoptosis and proliferation in tumors, resulted in no improvement in survival in transgenic animal models of colorectal cancer driven by APC and PTEN inactivation and KRAS G12D (PMID: 26206338). 26206338
APC inact mut KRAS G12D PTEN inact mut colorectal cancer sensitive BEZ235 + Binimetinib Preclinical Actionable In a preclinical study, combination of BEZ235 and Binimetinib (MEK162) increased survival compared to single agent in transgenic animal models of colorectal cancer driven by APC and PTEN inactivation and KRAS G12D (PMID: 26206338). 26206338
APC inact mut PTEN inact mut colorectal cancer sensitive BEZ235 Preclinical Actionable In a preclinical study, BEZ235 inhibited PI3K/mTOR signaling in tumors and increased survival in transgenic animal models of colorectal cancer driven by APC and PTEN inactivation (PMID: 26206338). 26206338
APC inact mut KRAS G12D PTEN inact mut colorectal cancer sensitive BEZ235 Preclinical Actionable In a preclinical study, BEZ235 inhibited mTOR signaling in tumors and increased survival in transgenic animal models of colorectal cancer driven by APC and PTEN inactivation, and KRAS G12D (PMID: 26206338). 26206338
APC inact mut KRAS G12D colorectal cancer sensitive BEZ235 + Binimetinib Preclinical Actionable In a preclinical study, combination of BEZ235 and Binimetinib (MEK162) resulted in reduced tumor growth and additive effect on survival compared to single agent in transgenic animal models of colorectal cancer driven by APC inactivation and KRAS G12D (PMID: 26206338). 26206338
APC inact mut PTEN inact mut colorectal cancer no benefit BEZ235 + Binimetinib Preclinical Actionable In a preclinical study, combination of BEZ235 and Binimetinib (MEK162) did not improve survival compared to single agent in transgenic animal models of colorectal cancer driven by APC and PTEN inactivation (PMID: 26206338). 26206338
APC inact mut PTEN inact mut colorectal cancer no benefit Binimetinib Preclinical Actionable In a preclinical study, Binimetinib (MEK162) reduced proliferation in tumors acutely but did not improve survival in transgenic animal models of colorectal cancer driven by APC and PTEN inactivation (PMID: 26206338). 26206338