21598290cd180953-sup-207185_2_supp_5379346_pnfwr8.xlsx (166.84 kB)

Supplementary Table 4 from Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel AKT1 Fusion–Driven Cancer

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posted on 2023-04-03, 21:42 authored by 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

Supplementary Table 4

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NCI

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ARTICLE ABSTRACT

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 AKT genes. A 12-year-old female with a histopathologically indeterminate epithelioid neoplasm was found to harbor a novel fusion between the LAMTOR1 and AKT1 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. This study describes the patient-driven discovery of the first AKT1 fusion–driven cancer and its treatment with the AKT inhibitor ipatasertib. Patient-derived in vitro and in vivo model systems are used to confirm the LAMTOR1–AKT1 fusion as a tumorigenic driver and identify potential mechanisms of resistance to AKT inhibition.This article is highlighted in the In This Issue feature, p. 565

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Keywords

Drug Targets Pediatric Cancers Translational Research

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CC BY

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