Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, POSITRON-EMISSION-TOMOGRAPHY, KIT MUTATIONS, MECHANISMS, CANCER, PTEN, RESISTANCE, MODEL, PATHWAYS, MESYLATE, THERAPY, Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Benzamides, Cell Line, Tumor, Cell Proliferation, Female, Gastrointestinal Neoplasms, Gastrointestinal Stromal Tumors, Genotype, Humans, Imatinib Mesylate, Indazoles, Mice, Phosphoinositide-3 Kinase Inhibitors, Piperazines, Proto-Oncogene Proteins c-kit, Pyrimidines, Signal Transduction, Sulfonamides, Tumor Burden, Xenograft Model Antitumor Assays, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, 3202 Clinical sciences, 3211 Oncology and carcinogenesis

Abstract:

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 = 136) were grafted bilaterally with human GIST carrying diverse KIT mutations. Mice were orally dosed over four weeks, grouped as follows: (A) control; (B) GDC-0941; (C) imatinib, and (D) GDC+IMA treatments. Xenografts regrowth after treatment discontinuation was assessed 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: In all models, GDC-0941 caused tumor growth stabilization, inhibiting tumor cell 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 regrowth assays confirmed superior activity of GDC+IMA over imatinib; in three 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 imatinib. Notably, after treatment withdrawal, tumor regression was sustained in tumors exposed to GDC+IMA, which was not observed under imatinib. Assessment of PTEN status may represent a useful predictive biomarker for patient selection.