Genetic alterations in the phosphoinositide 3-kinase/Akt signaling pathway confer sensitivity of thyroid cancer cells to therapeutic targeting of Akt and mammalian target of rapamycin.

Abstract

We investigated the genotype-dependent therapeutic potential of targeting the phosphoinositide 3-kinase (PI3K)/Akt pathway for thyroid cancer. Proliferation of TPC1, Hth7, FTC133, OCUT1, K1, and BCPAP cells that harbored PI3K/Akt-activating genetic alterations was potently inhibited by the Akt inhibitor perifosine, whereas SW1736, Hth74, WRO, KAT18, and TAD2 cells that harbored no genetic alterations had no or only modest responses. Inhibition of Akt phosphorylation by perifosine was seen in these cells. Genetic-dependent apoptosis was induced by perifosine in cells selectively tested. Similarly, potent inhibition of cell proliferation by the mammalian target of rapamycin (mTOR) inhibitor temsirolimus occurred in virtually all the cells harboring genetic alterations, whereas modest inhibition was seen in some of the cells not harboring genetic alterations. Temsirolimus inhibited the phosphorylation of p70S6K, a substrate of mTOR. Knockdown of Akt1/2 or mTOR by shRNA approach inhibited the proliferation and colony formation of FTC133 and OCUT1 cells that harbored genetic alterations in the PI3K/Akt pathway but had no effect on SW1736 and KAT18 cells that did not. Transfection with PIK3CA mutants greatly sensitized SW1736 cells to perifosine and temsirolimus. Growth of xenograft tumors derived from FTC133 cells but not SW1736 cells in nude mice was dramatically inhibited by perifosine. Thus, this work for the first time shows that genetic alterations in the PI3K/Akt pathway confer thyroid cancer cells addiction to this pathway and their sensitivity to inhibition by targeting Akt and mTOR. This genotype-based targeting of the PI3K/Akt pathway using Akt and mTOR inhibitors may offer an effective therapeutic strategy for thyroid cancer and warrants further studies.

• Authors: Dingxie Liu, Peng Hou, Zhi Liu, Guojun Wu, Mingzhao Xing
• Journal: Cancer research (Cancer Res) Vol. 69 Issue 18 Pg. 7311-9 (Sep 15 2009) ISSN: 1538-7445 [Electronic] United States
• PMID: 19706758 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Phosphoinositide-3 Kinase Inhibitors
• RNA, Small Interfering
• Phosphorylcholine
• perifosine
• temsirolimus
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• Oncogene Protein v-akt
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Animals
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Class I Phosphatidylinositol 3-Kinases
• Humans
• Mice
• Mice, Nude
• Oncogene Protein v-akt (antagonists & inhibitors, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (biosynthesis, genetics, metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylcholine (analogs & derivatives, pharmacology)
• Protein Kinases (metabolism)
• RNA, Small Interfering (genetics)
• Signal Transduction (genetics)
• Sirolimus (analogs & derivatives, pharmacology)
• TOR Serine-Threonine Kinases
• Thyroid Neoplasms (drug therapy, enzymology, genetics, pathology)
• Transfection
• Xenograft Model Antitumor Assays