A potent combination of the novel PI3K inhibitor, GDC-0941, with imatinib in gastrointestinal stromal tumor xenografts: long-lasting responses after treatment withdrawal

Purpose: Oncogenic signaling in gastrointestinal stromal tumors (GIST) is sustained via PI3K/AKT pathway. We used a panel of six GIST xenograft models to assess efficacy of GDC-0941 as single agent or in combination with imatinib (IMA). Experimental Design: Nude mice (n ¼ 136) were grafted bilaterally with human GIST carrying diverse KITmutations.Micewereorallydosedoverfourweeks,groupedasfollows:(A)control;(B)GDC-0941;(C) imatinib,and(D)GDCþIMAtreatments.Xenograftsregrowthaftertreatmentdiscontinuationwasassessed in groups C and D for an additional four weeks. Tumor response was assessed by volume measurements, micro-PET imaging, histopathology, and immunoblotting. Moreover, genomic alterations in PTEN/PI3K/ AKT pathway were evaluated. Results:Inallmodels,GDC-0941causedtumorgrowthstabilization,inhibitingtumorcellproliferation, but did not induce apoptosis. Under GDCþIMA, profound tumor regression, superior to either treatment alone, was observed. This effect was associated with the best histologic response, a nearly complete proliferation arrest and increased apoptosis. Tumor regrowth assays confirmed superior activity of GDCþIMA over imatinib; in three of six models, tumor volume remained reduced and stable even after treatment discontinuation. A positive correlation between response to GDCþIMA and PTEN loss, both on gene and protein levels, was found.