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Cancer Discovery
Cancer Discovery

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

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 and Stephen S. Roberts
Emily K. Slotkin
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Emily K. Slotkin
  • For correspondence: slotkine@mskcc.org
Daniel Diolaiti
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Neerav N. Shukla
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Filemon S. Dela Cruz
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Jennifer J. Clark
Rocky Mountain Hospital for Children, Denver, Colorado.
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Gunes Gundem
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Venkata D. Yellapantula
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Max F. Levine
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Daoqi You
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Peilin Ma
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Sagarika Pachhal
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Glorymar Ibanez Sanchez
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Ryma Benayed
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Achim A. Jungbluth
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Lillian M. Smyth
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Audrey Mauguen
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Irena Gushterova
Columbia University Medical Center, New York, New York.
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Hongxu Ding
Columbia University Medical Center, New York, New York.
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Lee Spraggon
Oxford Genetics, Oxford, United Kingdom.
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Robert Darnell
New York Genome Center, New York, New York.
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Andrea Califano
Columbia University Medical Center, New York, New York.
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Marc Ladanyi
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Elli Papaemmanuil
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Andrew L. Kung
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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David M. Hyman
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Stephen S. Roberts
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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DOI: 10.1158/2159-8290.CD-18-0953 Published May 2019
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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

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received August 23, 2018.
  • Revision received January 18, 2019.
  • Accepted March 12, 2019.
  • Published first March 15, 2019.
  • ©2019 American Association for Cancer Research.
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Cancer Discovery: 9 (5)
May 2019
Volume 9, Issue 5
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Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel AKT1 Fusion–Driven Cancer
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 and Stephen S. Roberts
Cancer Discov May 1 2019 (9) (5) 605-616; DOI: 10.1158/2159-8290.CD-18-0953

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Patient-Driven Discovery, Therapeutic Targeting, and Post-Clinical Validation of a Novel AKT1 Fusion–Driven Cancer
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 and Stephen S. Roberts
Cancer Discov May 1 2019 (9) (5) 605-616; DOI: 10.1158/2159-8290.CD-18-0953
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