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

AKT mediated Cell growth scheme

AKT Mediated Cell Growth Scheme (https://creativecommons.org/licenses/by/4.0/

Slotkin EK, Diolaiti D, Shukla NN, Dela Cruz FS, Clark JJ, Gundem G, Yellapantula VD, Levine MF, You D, Ma P, Pachhal S, Ibanez Sanchez G, Benayed R, Jungbluth AA, Smyth LM, Mauguen A, Gushterova I, Ding H, Spraggon L, Darnell R, Califano A, Ladanyi M, Papaemmanuil E, Kung AL, Hyman DM, Roberts SS

Cancer Discovery

March 15, 2019

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.

Program:
CTD²
Last updated: March 25, 2019