Thursday, May 24, 2012
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
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
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