Journal
CANCER DISCOVERY
Volume 9, Issue 5, Pages 605-616Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-0953
Keywords
-
Categories
Funding
- Sohn Conference Foundation
- PaulieStrong Foundation
- Cycle for Survival
- Olayan Precision Pediatrics Program
- NCI [P30 CA008748]
- NCI Cancer Target Discovery and Development Program [U01 CA217858]
- NCI Outstanding Investigator Award [R35 CA197745]
- NIH Shared Instrumentation Grants [S10 OD012351, S10 OD021764]
Ask authors/readers for more resources
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available