Reference Detail

Ref Type

Journal Article

PMID

(21325073)

Authors

Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I

Title

Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Clinical cancer research : an official journal of the American Association for Cancer Research	17	10	2011 May 15	3193-203	Clin Cancer Res

URL

Abstract Text

The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor.In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy.In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (∼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor).Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587.

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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
Gedatolisib	Gedatolisib	13	4

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Gedatolisib		PKI-587\|PF-05212384\|PF 05212384	mTOR Inhibitor 51 PI3K Inhibitor (Pan) 42	Gedatolisib (PF-05212384) is an ATP-competitive inhibitor that targets phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, and may result in antitumor activity, including inhibition of tumor growth and tumor regression (PMID: 21325073, PMID: 31822716).

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 H1047R	breast cancer	sensitive	Gedatolisib	Preclinical	Actionable	In a preclinical study, Gedatolisib (PKI-587) inhibited growth of human breast cancer cells harboring PIK3CA H1047R in culture (PMID: 21325073, PMID: 17314276).	17314276 21325073
PTEN loss	brain glioma	sensitive	Gedatolisib	Preclinical	Actionable	In a preclinical study, Gedatolisib (PKI-587) inhibited growth of human glioma cells with PTEN loss in culture (PMID: 21325073).	21325073
TP53 R158G	lung non-small cell carcinoma	sensitive	Gedatolisib	Preclinical	Actionable	In a preclinical study, Gedatolisib (PKI-587) inhibited growth of human non-small cell lung carcinoma cells harboring TP53 R158G in culture (PMID: 21325073, PMID: 23980093).	21325073 23980093
NRAS Q61K	lung non-small cell carcinoma	decreased response	Gedatolisib	Preclinical	Actionable	In a preclinical study, human non-small cell lung cancer cells harboring NRAS Q61K had a decreased response to Gedatolisib (PKI-587) in culture (PMID: 21325073, PMID: 12068308).	21325073 12068308
PTEN del	prostate cancer	sensitive	Gedatolisib	Preclinical	Actionable	In a preclinical study, Gedatolisib (PKI-587) inhibited growth of human prostate cancer cells harboring PTEN deletion in culture (PMID: 21325073, PMID: 14737113).	14737113 21325073
PTEN A72fs	breast cancer	sensitive	Gedatolisib	Preclinical	Actionable	In a preclinical study, Gedatolisib (PKI-587) inhibited growth of human breast cancer cells harboring PTEN A72fs*5 in culture (PMID: 21325073, PMID: 17314276).	17314276 21325073
PTEN loss	renal carcinoma	decreased response	Gedatolisib	Preclinical	Actionable	In a preclinical study, human renal carcinoma cells with PTEN loss had a decreased response to Gedatolisib (PKI-587) in culture (PMID: 21325073).	21325073
PIK3CA E545K	breast cancer	sensitive	Gedatolisib	Preclinical	Actionable	In a preclinical study, Gedatolisib (PKI-587) inhibited growth of human breast cancer cells harboring PIK3CA E545K in culture (PMID: 21325073, PMID: 17314276).	17314276 21325073
BRAF V600E	colon cancer	sensitive	Gedatolisib	Preclinical	Actionable	In a preclinical study, Gedatolisib (PKI-587) inhibited Braf V600E in vitro and inhibited growth of human colon cancer cells harboring BRAF V600E in culture (PMID: 21325073, PMID: 24042735).	24042735 21325073
PTEN loss VHL loss	renal carcinoma	decreased response	Gedatolisib	Preclinical	Actionable	In a preclinical study, human renal carcinoma cells with PTEN loss and VHL loss had a decreased response to Gedatolisib (PKI-587) in culture (PMID: 21325073).	21325073