Recent achievements in the development of multitargeted molecular inhibitors necessitate a better understanding of the contribution of activity against individual targets to their efficacy.
SU11248, a small-molecule inhibitor targeting class III/V
receptor tyrosine kinases, including the
platelet-derived growth factor (PDGF) and
vascular endothelial growth factor (
VEGF) receptors, KIT and FLT3, exhibits direct effects on
cancer cells as well as antiangiogenic activity. Here, we investigated the contributions of inhibiting individual
SU11248 target receptors to its overall antitumor efficacy in
tumor models representing diverse signaling paradigms. Consistent with previous results,
SU11248 was highly efficacious (frequently cytoreductive) in all models tested. To elucidate the specific contributions of inhibition of PDGF and
VEGF receptors to the in vivo efficacy of
SU11248, we employed two selective inhibitors,
SU10944 (
VEGF receptor inhibitor) and
Gleevec (
PDGF receptor inhibitor).
SU10944 alone induced a
tumor growth delay in all models evaluated, consistent with a primarily antiangiogenic mode of action. In contrast,
Gleevec resulted in modest growth inhibition in
tumor models in which the
cancer cells expressed its targets (PDGFRbeta and KIT), but was not efficacious against
tumors not driven by these target
receptor tyrosine kinases. Strikingly, in all but one
tumor model evaluated, the antitumor efficacy of
SU10944 combined with
Gleevec was similar to that of single-agent
SU11248, and was greatly superior to that of each compound alone, indicating that the antitumor potency of
SU11248 in these models stems from combined inhibition of both PDGF and
VEGF receptors. The one exception was a model driven by an activated mutant of FLT3, in which the activity of
SU11248, which targets FLT3, was greater than that of
SU10944 plus
Gleevec. Moreover,
SU10944 combined with
Gleevec inhibited
tumor neoangiogenesis to an extent comparable to that of
SU11248. Thus, the potent efficacy of
SU11248 in models representing diverse signaling paradigms results from simultaneous inhibition of individual target receptors expressed both in
cancer cells and in the
tumor neovasculature, supporting the hypothesis that multitargeted inhibitors have the cumulative antitumor efficacy of combined single-target inhibitors.