Reference Detail

Ref Type Journal Article
PMID (25637314)
Authors Foster P, Yamaguchi K, Hsu PP, Qian F, Du X, Wu J, Won KA, Yu P, Jaeger CT, Zhang W, Marlowe CK, Keast P, Abulafia W, Chen J, Young J, Plonowski A, Yakes FM, Chu F, Engell K, Bentzien F, Lam ST, Dale S, Yturralde O, Matthews DJ, Lamb P, Laird AD
Title The Selective PI3K Inhibitor XL147 (SAR245408) Inhibits Tumor Growth and Survival and Potentiates the Activity of Chemotherapeutic Agents in Preclinical Tumor Models.
Journal Molecular cancer therapeutics
Vol 14
Issue 4
Date 2015 Apr
URL
Abstract Text Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, β, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
XL147 Pilaralisib (XL147) is an inhibitor of all class I PI3Ks, thereby blocking activation of the PI3K signaling pathway and potentially resulting in antitumor activity including inhibition of cell proliferation, cell invasion, and tumor growth (PMID: 25637314).
Drug Name Trade Name Synonyms Drug Classes Drug Description
XL147 SAR245408|Pilaralisib PI3K Inhibitor (Pan) 34 Pilaralisib (XL147) is an inhibitor of all class I PI3Ks, thereby blocking activation of the PI3K signaling pathway and potentially resulting in antitumor activity including inhibition of cell proliferation, cell invasion, and tumor growth (PMID: 25637314).
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
KRAS Q61K non-small cell lung carcinoma sensitive XL147 Preclinical - Cell line xenograft Actionable In a preclinical study, XL147 inhibited tumor growth and vascularization in xenograft models of a human non-small cell lung cancer cell line harboring KRAS Q61K (PMID: 25637314). 25637314
KRAS Q61K non-small cell lung carcinoma sensitive XL147 + Carboplatin Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of XL147 and Paraplatin (carboplatin) inhibited tumor growth and angiogenesis in xenograft models of a human non-small cell lung cancer cell line harboring KRAS Q61K, with increased efficacy compared to either agent alone (PMID: 25637314). 25637314
PTEN V54fs glioblastoma multiforme sensitive XL147 Preclinical - Cell line xenograft Actionable In a preclinical study, XL147 inhibited tumor growth in xenograft models of a human glioblastoma cell line harboring PTEN V54fs (PMID: 25637314). 25637314
BRAF V600E PTEN loss melanoma sensitive XL147 Preclinical - Cell line xenograft Actionable In a preclinical study, XL147 inhibited tumor growth in xenograft models of a PTEN-deficient human melanoma cell line harboring BRAF V600E (PMID: 25637314). 25637314
KRAS G12S STK11 inact mut non-small cell lung carcinoma sensitive XL147 Preclinical - Cell line xenograft Actionable In a preclinical study, XL147 inhibited tumor growth in xenograft models of a human non-small cell lung cancer cell line harboring KRAS G12S and an STK11(LKB) inactivating mutation (PMID: 25637314). 25637314
PTEN inact mut prostate adenocarcinoma sensitive XL147 + Paclitaxel Preclinical - Cell line xenograft Actionable In a preclinical study, the combination of XL147 and Taxol (paclitaxel) inhibited tumor growth and angiogenesis in xenograft models of a human prostate adenocarcinoma cell line harboring an inactivating mutation in PTEN, with increased efficacy compared to either agent alone (PMID: 25637314). 25637314
BRAF V600D PTEN loss melanoma sensitive XL147 Preclinical - Cell line xenograft Actionable In a preclinical study, XL147 inhibited tumor growth in xenograft models of a PTEN-deficient human melanoma cell line harboring BRAF V600D (PMID: 25637314). 25637314
MET over exp melanoma sensitive XL147 Preclinical Actionable In a preclinical study, XL147 inhibited migration and growth of mouse melanoma cells with MET over expression in culture (PMID: 25637314). 25637314
BRAF mutant Advanced Solid Tumor decreased response XL147 Preclinical Actionable In a preclinical study, tumor cell lines harboring BRAF mutations demonstrated limited sensitivity to XL147 treatment in culture (PMID: 25637314). 25637314
PTEN inact mut prostate adenocarcinoma sensitive XL147 Preclinical - Cell line xenograft Actionable In a preclinical study, XL147 inhibited PI3K signaling, growth, and migration of a human prostate adenocarcinoma cell line harboring a PTEN inactivating mutation in culture, and inhibited tumor growth and vascularization in xenograft models (PMID: 25637314). 25637314