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	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	4	2015 Apr	931-40	Mol Cancer Ther

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	Drugs	Efficacy Evidence	Clinical Trials
XL147	XL147	9	1

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
XL147		SAR245408\|Pilaralisib\|XL-147	PI3K Inhibitor (Pan) 42	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 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
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
PTEN V54fs	glioblastoma	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
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
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
PTEN inact mut	prostate adenocarcinoma	sensitive	Paclitaxel + XL147	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 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
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