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Ref Type | Journal Article | ||||||||||||
PMID | (22662154) | ||||||||||||
Authors | Shoji K, Oda K, Kashiyama T, Ikeda Y, Nakagawa S, Sone K, Miyamoto Y, Hiraike H, Tanikawa M, Miyasaka A, Koso T, Matsumoto Y, Wada-Hiraike O, Kawana K, Kuramoto H, McCormick F, Aburatani H, Yano T, Kozuma S, Taketani Y | ||||||||||||
Title | Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. | ||||||||||||
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Abstract Text | The PI3K (phosphatidylinositol-3-kinase)/mTOR (mammalian target of rapamycin) pathway is frequently activated in endometrial cancer through various PI3K/AKT-activating genetic alterations. We examined the antitumor effect of NVP-BEZ235--a dual PI3K/mTOR inhibitor--and RAD001--an mTOR inhibitor--in 13 endometrial cancer cell lines, all of which possess one or more alterations in PTEN, PIK3CA, and K-Ras. We also combined these compounds with a MAPK pathway inhibitor (PD98059 or UO126) in cell lines with K-Ras alterations (mutations or amplification). PTEN mutant cell lines without K-Ras alterations (n = 9) were more sensitive to both RAD001 and NVP-BEZ235 than were cell lines with K-Ras alterations (n = 4). Dose-dependent growth suppression was more drastically induced by NVP-BEZ235 than by RAD001 in the sensitive cell lines. G1 arrest was induced by NVP-BEZ235 in a dose-dependent manner. We observed in vivo antitumor activity of both RAD001 and NVP-BEZ235 in nude mice. The presence of a MEK inhibitor, PD98059 or UO126, sensitized the K-Ras mutant cells to NVP-BEZ235. Robust growth suppression by NVP-BEZ235 suggests that a dual PI3K/mTOR inhibitor is a promising therapeutic for endometrial carcinomas. Our data suggest that mutational statuses of PTEN and K-Ras might be useful predictors of sensitivity to NVP-BEZ235 in certain endometrial carcinomas. |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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PIK3CA R108H PTEN mut | endometrial cancer | sensitive | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 inhibited proliferation of endometrial cancer cells harboring PIK3CA R108H and PTEN mutations in culture (PMID: 22662154). | 22662154 |
PTEN mutant | endometrial cancer | sensitive | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 decreased growth of endometrial cancer cells harboring a PTEN nonsense mutation in culture and in xenograft models (PMID: 22662154). | 22662154 |
PIK3CA E365K PTEN mut | endocervical carcinoma | sensitive | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 inhibited proliferation of endometrial cancer cells harboring PIK3CA E365K and PTEN mutations in culture (PMID: 22662154). | 22662154 |
PIK3CA R38C PTEN mut | endometrial cancer | sensitive | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 decreased growth of endometrial cancer cells harboring PIK3CA R38C and PTEN mutations in culture and in xenograft models (PMID: 22662154). | 22662154 |
PIK3CA E365K PTEN mut | endometrial cancer | sensitive | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 inhibited proliferation of endometrial cancer cells harboring PIK3CA E365K and PTEN mutations in culture (PMID: 22662154). | 22662154 |
PIK3CA R88Q PTEN mut | endometrial cancer | sensitive | Everolimus | Preclinical | Actionable | In a preclinical study, Afinitor (everolimus) inhibited proliferation of endometrial cancer cells harboring PIK3CA R88Q and PTEN mutations in culture (PMID: 22662154). | 22662154 |
PTEN mutant | endometrial cancer | sensitive | Everolimus | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Afinitor (everolimus) inhibited growth of endometrial cancer cells harboring a PTEN nonsense mutation in culture and in xenograft models (PMID: 22662154). | 22662154 |
PIK3CA R88Q PTEN mut | endometrial cancer | sensitive | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 inhibited proliferation of endometrial cancer cells harboring PIK3CA R88Q and PTEN mutations in culture (PMID: 22662154). | 22662154 |