mTOR kinase inhibitor potentiates apoptosis of PI3K and MEK inhibitors in diagnostically defined subpopulations.
The mammalian target of rapamycin (mTOR) is a central node in a complex signaling network that is regulated by several pathways deregulated in human cancers, including the PI3K/Akt and MAPK pathways. Targeting mTOR therefore presents an opportunity for therapeutic intervention. However, mTOR inhibition with rapamycin analogs or kinase inhibitors reduces cell growth but does not induce apoptosis, and the clinical benefit of rapamycin analogs has been modest. In this study we show that mTOR kinase inhibitors can potentiate apoptosis when used in combination with upstream targeted agents such as PI3K and MEK inhibitors. This increased apoptosis is dependent on genetic background, and correlates with active growth factor survival pathways. In PI3K mutant tumors, mTOR inhibition leads to partial reactivation of Akt which allows cells to survive, whereas in KRAS mutant tumors, this same reactivation of Akt occurs but is not required for cell survival. These data suggest the use of selected rational combinations of mTOR kinase inhibitors with other targeted inhibitors in specific tumor genotypes to achieve the maximal cytotoxic response by inhibiting two nodes in the activated signaling network.
Department of Cancer Signaling and Translational Oncology, Genentech, Inc., South San Francisco, CA 94080, United States.
Ulka
U
Vijapurkar
Liliane
L
Robillard
Siqun
S
Zhou
Michael
M
Degtyarev
Kui
K
Lin
Tom
T
Truong
Jarrod
J
Tremayne
Leanne Berry
LB
Ross
Zhonghua
Z
Pei
Lori S
LS
Friedman
Elizabeth M
EM
Blackwood
Marcia
M
Belvin
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; D020930:MAP Kinase Kinase Kinases