Rationale Idiopathic pulmonary fibrosis (IPF) is the
most rapidly progressive and fatal of all fibrotic
conditions with no curative therapies. Common
pathomechanisms between IPF and cancer are
increasingly recognised, including dysfunctional pan-PI3
kinase (PI3K) signalling as a driver of aberrant
proliferative responses. GSK2126458 is a novel, potent,
PI3K/mammalian target of rapamycin (mTOR) inhibitor
which has recently completed phase I trials in the
oncology setting. Our aim was to establish a scientific
and dosing framework for PI3K inhibition with this agent
in IPF at a clinically developable dose.
Methods We explored evidence for pathway signalling
in IPF lung tissue and examined the potency of
GSK2126458 in fibroblast functional assays and
precision-cut IPF lung tissue. We further explored the
potential of IPF patient-derived bronchoalveolar lavage
(BAL) cells to serve as pharmacodynamic biosensors to
monitor GSK2126458 target engagement within the
lung.
Results We provide evidence for PI3K pathway
activation in fibrotic foci, the cardinal lesions in IPF.
GSK2126458 inhibited PI3K signalling and functional
responses in IPF-derived lung fibroblasts, inhibiting Akt
phosphorylation in IPF lung tissue and BAL derived cells
with comparable potency. Integration of these data with
GSK2126458 pharmacokinetic data from clinical trials in
cancer enabled modelling of an optimal dosing regimen
for patients with IPF.
Conclusions Our data define PI3K as a promising
therapeutic target in IPF and provide a scientific and
dosing framework for progressing GSK2126458 to
clinical testing in this disease setting. A proof-ofmechanism
trial of this agent is currently underway.