Patient-driven discovery, therapeutic targeting, and post-clinical validation of a novel AKT1 fusion-driven cancer Journal Article
| Authors: | Slotkin, E. K.; Diolaiti, D.; Shukla, N. N.; Dela Cruz, F. S.; Clark, J. J.; Gundem, G.; Yellapantula, V. D.; Levine, M. F.; You, D.; Ma, P.; Pachhal, S.; Ibanez Sanchez, G.; Benayed, R.; Jungbluth, A. A.; Smyth, L. M.; Mauguen, A.; Gushterova, I.; Ding, H.; Spraggon, L.; Darnell, R.; Califano, A.; Ladanyi, M.; Papaemmanuil, E.; Kung, A. L.; Hyman, D. M.; Roberts, S. S. |
| Article Title: | Patient-driven discovery, therapeutic targeting, and post-clinical validation of a novel AKT1 fusion-driven cancer |
| 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. ©2019 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 9 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2019-05-01 |
| Start Page: | 605 |
| End Page: | 616 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-18-0953 |
| PUBMED: | 30877085 |
| PROVIDER: | scopus |
| PMCID: | PMC6497560 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 June 2019 -- Source: Scopus |
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