A Potent Combination of the Novel PI3K Inhibitor, GDC-0941, with Imatinib in Gastrointestinal Stromal Tumor Xenografts: Long-Lasting Responses after Treatment Withdrawal

Abstract

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.

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

“…A growing body of evidence now suggests that targeting multiple pathways by means of combination treatment may be a more beneficial approach. Given the success observed with PI3K inhibitors in combination with IM in GIST models (13,14), we set out to examine the effects of combined inhibition of AKT (a downstream effector of PI3K) and KIT in a panel of IM-sensitive and -resistant GIST cell lines. We selected MK-2206, a highly selective, allosteric, pan-AKT inhibitor for our combination studies.…”

“…Clinical trials are currently underway to investigate the use of PI3K/AKT inhibitors in combination with RTK inhibitors in CLL, melanoma, and NSCLC. Recently, PI3K inhibitors were combined with IM in preclinical studies using GIST xenografts, and this combination demonstrated superior and more durable responses as compared to either single agent (13,14). Reduced or absent expression of the phosphatase and tensin homolog (PTEN) was significantly associated with IM treatment in GIST patient samples, and PTEN deficiency in vitro results in hyperactivation of AKT (9).…”

“…This approach was recently tested in two preclinical studies evaluating IM in combination with PI3K inhibitors (PI3Ki) in GIST xenograft models (13,14). In the first study (2013), a pan-inhibitor of class I PI3K, called GDC-0941, was administered as a single agent or in combination with IM to a panel of IM-sensitive and -resistant xenografts (14).…”

“…In the first study (2013), a pan-inhibitor of class I PI3K, called GDC-0941, was administered as a single agent or in combination with IM to a panel of IM-sensitive and -resistant xenografts (14). GDC-0941 led to stable disease in a subset of these models (dependent on mutational status), whereas the combination of GDC-0941 and IM actually induced tumor shrinkage.…”

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

“…10 Recent preclinical in vivo studies performed on GIST xenografts, using PI3K inhibitors in combination with imatinib, indicated synergistic and long-lasting effects, and suggested that PTEN inactivation could have an impact on the response to this therapy. 11,12 Yet, currently no studies have been performed to investigate the range of PTEN abnormities in imatinib-resistant GIST patients.…”