Box 1. Heartless PI3K inhibition.

A study published in Science Translational Medicine by researchers from the State University of New York at Stony Brook showed that blocking phosphoinositide 3-kinase-a (PI3Ka) signaling in the heart triggered prolongation of the QT interval in mice and in cultured canine ventricular myocytes.12

In mice, cardiac-specific knockout of Pi3ka led to increased action potential duration (APD) compared with that seen in wild-type animals, whereas cardiac-specific knockout of Pi3kb had minimal effects on APD. When the Pi3kb knockout mice were treated with a PI3Ka inhibitor, the animals showed APD length comparable to that in the Pi3ka knockout mice.

Moreover, echocardiogram (ECG) readings of hearts isolated from the Pi3ka knockout mice showed the QT interval was almost twice as long as that in wild-type controls. In cultured canine myocytes, Novartis AG's PI3Ka and mammalian target of rapamycin (mTOR; FRAP; RAFT1) dual inhibitor, BEZ235, increased APD compared with vehicle.

Those results suggest that in the mouse heart, reduced signaling by the Pi3ka isoform solely mediates APD prolongation.

The authors concluded that patients treated with PI3K inhibitors and other drugs targeting PI3K signaling in the heart "should be closely monitored for QT prolongation and cardiac arrhythmias."

Corresponding author Richard Lin told SciBX that he and corresponding author Ira Cohen "are actively investigating how to counter the off-target proarrhythmic effect caused by PI3K inhibitors and other drugs that inhibit PI3K signaling." He declined to provide additional details.

Lin and Cohen are professors of physiology and biophysics at SUNY Stony Brook. Cohen also is director of the university's Institute of Molecular Cardiology.

Both PI3Ka-selective inhibitors and PI3Ka and mTOR dual inhibitors are in the clinic.

PI3Ka-selective inhibitors include GDC-0941 from Roche, which is in Phase II testing for breast cancer, and BYL719 from Novartis and INK1117 from Takeda Pharmaceutical Co. Ltd., both of which are in Phase I testing for solid tumors.

PI3Ka and mTOR dual inhibitors include BEZ235 from Novartis, which is in Phase I/II testing for solid cancers; XL765 from Exelixis Inc. and Sanofi, which is in Phase Ib/II testing for gliomas and solid tumors; and PWT33597 from Pathway Therapeutics Inc., which is in Phase I testing for solid tumors.

None of the companies responded to requests for comment.

However, data presented at the 2009 and 2010 American Society of Clinical Oncology and American Association of Cancer Research meetings showed that BEZ235 had no dose-limiting toxicities and had mild adverse events including nausea, diarrhea and anemia. XL765 also showed good tolerability with adverse events similar to those of BEZ235.13