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|Ref Type||Journal Article|
|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|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|XL147||SAR245408|Pilaralisib|XL-147||PI3K Inhibitor (Pan) 38||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, PMID: 29593099).|
|Gene||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|
|PIK3CA amp||ovarian cancer||sensitive||XL147||Preclinical - Cell line xenograft||Actionable||In a preclinical study, XL147 inhibited PI3K signaling and proliferation of a PIK3CA amplified human ovarian cancer cell line in culture, and inhibited tumor growth in xenograft models (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|
|PIK3CA mutant||Advanced Solid Tumor||sensitive||XL147||Preclinical||Actionable||In a preclinical study, tumor cell lines with PIK3CA mutations demonstrated sensitivity to XL147 in culture (PMID: 25637314).||25637314|
|PIK3CA E545K||breast carcinoma||sensitive||XL147||Preclinical - Cell line xenograft||Actionable||In a preclinical study, XL147 inhibited PI3K signaling and proliferation of a human breast carcinoma cell line harboring PIK3CA E545K in culture and inhibited tumor growth in xenograft models (PMID: 25637314).||25637314|