Signaling pathway screening platforms are an efficient approach toidentify therapeutic targets in precision-medicine oriented early phaseclinical trials

Abstract

Precision medicine aims to tailor cancer therapies to target specific tumorpromoting aberrations. For tumors that lack actionable drivers, extensive molecular characterization and pre-clinical drug efficacy studies will be required to match patients with the appropriate targeted therapy. A cell line maintained at low passage and a patient-derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention. No actionable mutations were identified after whole exome sequencing of the patients DNA; however, whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, that include the PIK3CA and RICTOR genes, respectively. Consistent with amplification of these genes, pathway analysis revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated in the tumor biopsy-derived cell culture and PDX, and response to the AKT inhibitor AZD5363 was observed both in vitro and in vivo indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. In conclusion, our study demonstrates that high throughput signaling pathway analysis complements next-generation sequencing approaches for detection of actionable alterations and will aid in patient stratification into early-phase clinical trials.