Reference Detail

Ref Type

Journal Article

PMID

(21289267)

Authors

Liu R, Liu D, Trink E, Bojdani E, Ning G, Xing M

Title

The Akt-specific inhibitor MK2206 selectively inhibits thyroid cancer cells harboring mutations that can activate the PI3K/Akt pathway.

Journal	Vol	Issue	Date	Pages	Journal Short Title
The Journal of clinical endocrinology and metabolism	96	4	2011 Apr	E577-85	J Clin Endocrinol Metab

URL

Abstract Text

The phosphoinositide 3-kinase (PI3K)/Akt pathway is widely postulated to be an effective therapeutic target in thyroid cancer.The aim of the study was to test the therapeutic potential of the novel Akt inhibitor MK2206 for thyroid cancer.We examined the effects of MK2206 on thyroid cancer cells with respect to the genotypes of the PI3K/Akt pathway.Proliferation of thyroid cancer cells OCUT1, K1, FTC133, C643, Hth7, and TPC1, which harbored PIK3CA, PTEN, Ras, or RET/PTC mutations that could activate the PI3K/Akt pathway, was potently inhibited by MK2206 with IC(50) values mostly below or around 0.5 μm. In contrast, no potent inhibition by MK2206 was seen in most of the Hth74, KAT18, SW1736, WRO, and TAD2 cells that did not harbor mutations in the PI3K/Akt pathway. The inhibition efficacy was also genetic-selective. Specifically, the average inhibition efficacies were 59.2 ± 11.3 vs. 36.4 ± 8.8% (P = 0.005) at 1 μm MK2206 and 64.4 ± 11.5 vs. 38.5 ± 18.9% (P = 0.02) at 3 μm MK2206 for cells with mutations vs. cells without. The SW1736 cell, lacking mutations in the PI3K/Akt pathway, had minimal response to MK2206, but transfection with exogenous PIK3CA mutants, PIK3CA H1047R and E545K, significantly increased its sensitivity to MK2206. MK2206 also completely overcame the feedback activation of Akt from temsirolimus-induced mammalian target of rapamycin suppression, and the two inhibitors synergistically inhibited thyroid cancer cell growth.Our study demonstrates a genetic selectivity of MK2206 in inhibiting thyroid cancer cells by targeting the PI3K/Akt pathway, supporting a clinical trial in thyroid cancer.

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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

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

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	thyroid cancer	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 inhibited AKT activation, proliferation, and growth of thyroid cancer cell lines with PI3K/AKT pathway alterations in culture, including an anaplastic thyroid cancer cell line harboring PIK3CA H1047R (PMID: 21289267).	21289267
PIK3CA E545K	thyroid cancer	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, expression of PIK3CA E545K in a thyroid cancer cell line resulted in increased sensitivity to MK2206 in culture (PMID: 21289267).	21289267
PIK3CA E542K	papillary thyroid carcinoma	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 inhibited AKT activation, proliferation, and growth of thyroid cancer cell lines with PI3K/AKT pathway alterations in culture, including a papillary thyroid cancer cell line harboring PIK3CA E542K (PMID: 21289267).	21289267
PIK3CA E542K	papillary thyroid carcinoma	sensitive	MK2206 + Temsirolimus	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 suppressed activation of AKT induced by Torisel (temsirolimus), and MK2206 and Torisel (temsirolimus) demonstrated synergy in inhibiting growth of a papillary thyroid cancer cell line harboring PIK3CA E542K in culture (PMID: 21289267).	21289267
NRAS Q61R	thyroid cancer	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 inhibited AKT activation, proliferation, and growth of thyroid cancer cell lines with PI3K/AKT pathway alterations in culture, including an anaplastic thyroid cancer cell line harboring NRAS Q61R (PMID: 21289267).	21289267
HRAS G13R	thyroid cancer	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 inhibited AKT activation, proliferation, and growth of thyroid cancer cell lines with PI3K/AKT pathway alterations in culture, including an anaplastic thyroid cancer cell line harboring HRAS G13R (PMID: 21289267).	21289267
PIK3CA H1047R	thyroid cancer	sensitive	MK2206 + Temsirolimus	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 and Torisel (temsirolimus) demonstrated synergy in inhibiting growth of an anaplastic thyroid cancer cell line harboring PIK3CA H1047R in culture (PMID: 21289267).	21289267
PTEN R130*	follicular thyroid carcinoma	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, MK2206 inhibited AKT activation, proliferation, and growth of thyroid cancer cell lines with PI3K/AKT pathway alterations in culture, including an follicular thyroid cancer cell line harboring PTEN R130* and loss of one PTEN allele (PMID: 21289267).	21289267