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#30877085   2019/03/15 To Up

Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel Fusion-Driven Cancer.

Despite the important role of the PI3K/AKT/mTOR axis in the pathogenesis of cancer, to date there have been few functional oncogenic fusions identified involving the genes. A 12-year-old female with a histopathologically indeterminate epithelioid neoplasm was found to harbor a novel fusion between the and genes. Through expanded use access, she became the first pediatric patient to be treated with the oral ATP-competitive pan-AKT inhibitor ipatasertib. Treatment resulted in dramatic tumor regression, demonstrating through patient-driven discovery that the fusion resulted in activation of AKT1, was an oncogenic driver, and could be therapeutically targeted with clinical benefit. Post-clinical validation using patient-derived model systems corroborated these findings, confirmed a membrane-bound and constitutively active fusion protein, and identified potential mechanisms of resistance to single-agent treatment with ipatasertib. SIGNIFICANCE: This study describes the patient-driven discovery of the first AKT1 fusion-driven cancer and its treatment with the AKT inhibitor ipatasertib. Patient-derived and model systems are used to confirm the fusion as a tumorigenic driver and identify potential mechanisms of resistance to AKT inhibition..
Emily K Slotkin, Daniel Diolaiti, Neerav N Shukla, Filemon S Dela Cruz, Jennifer J Clark, Gunes Gundem, Venkata D Yellapantula, Max F Levine, Daoqi You, Peilin Ma, Sagarika Pachhal, Glorymar Ibanez Sanchez, Ryma Benayed, Achim A Jungbluth, Lillian M Smyth, Audrey Mauguen, Irena Gushterova, Hongxu Ding, Lee Spraggon, Robert Darnell, Andrea Califano, Marc Ladanyi, Elli Papaemmanuil, Andrew L Kung, David M Hyman, Stephen S Roberts

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