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Cancer Discov. 2019 May;9(5):605-616. doi: 10.1158/2159-8290.CD-18-0953. Epub 2019 Mar 15.

Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel AKT1 Fusion-Driven Cancer.

Author information

1
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York. slotkine@mskcc.org.
2
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
3
Rocky Mountain Hospital for Children, Denver, Colorado.
4
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
5
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
6
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
7
Columbia University Medical Center, New York, New York.
8
Oxford Genetics, Oxford, United Kingdom.
9
New York Genome Center, New York, New York.
#
Contributed equally

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. 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 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.

PMID:
30877085
PMCID:
PMC6497560
[Available on 2019-11-01]
DOI:
10.1158/2159-8290.CD-18-0953

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