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

Menée à l'aide de xénogreffes de tumeurs stromales gastro-intestinales, cette étude évalue l'activité antitumorale d'un composé appelé GDC-0941, un inhibiteur de la signalisation PI3K, seul ou en combinaison avec l'imatinib, en fonction du statut du gène PTEN

Résumé en anglais

Introduction: 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=136) were grafted bilaterally with human GIST carrying divers KIT mutations. Mice were orally dosed over four weeks, grouped as follows: A) control; B) GDC-0941; C) IMA and D) GDC+IMA treatments. Xenografts re-growth after treatment discontinuation was assessed in group C and D for 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: In all models, GDC-0941 caused tumor growth stabilization, inhibiting tumor cells proliferation but did not induce apoptosis. Under GDC+IMA, 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 re-growth assays confirmed superior activity of GDC+IMA over IMA; in three out of six models tumor volume remained reduced and stable even after treatment discontinuation. A positive correlation between response to GDC+IMA and PTEN loss, both on gene and protein levels, was found.

Conclusion: GDC+IMA has significant antitumor efficacy in GIST xenografts, inducing more substantial tumor regression, apoptosis and durable effects than IMA. Notably, after treatment withdrawal, tumor regression was sustained in tumors exposed to GDC+IMA, which was not observed under IMA. Assessment of PTEN status may represent a useful predictive biomarker for patient selection.