Enhanced efficacy of JAK1 inhibitor with mTORC1/C2 targeting in smoldering/chronic adult T cell leukemia

  • Transl Oncol. 2021 Jan;14(1):100913. doi: 10.1016/j.tranon.2020.100913.
Anusara Daenthanasanmak  1 ,  Yuquan Lin  1 ,  Meili Zhang  1 ,  Bonita R Bryant  1 ,  Michael N Petrus  1 ,  Richard N Bamford  2 ,  Craig J Thomas  3 ,  Milos D Miljkovic  1 ,  Kevin C Conlon  1 ,  Thomas A Waldmann  4
Affiliations
  • 1. Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1374, Bethesda, MD 20892, USA.
  • 2. Transponics, Essex Junction, VT 05452, USA.
  • 3. Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA.
  • 4. Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, MSC 1374, Bethesda, MD 20892, USA. Electronic address: [email protected].
PMID: 33129109 DOI: 10.1016/j.tranon.2020.100913
Abstract

Adult T-cell leukemia (ATL) is an aggressive T-cell lymphoproliferative malignancy of regulatory T lymphocytes (Tregs), caused by human T-cell lymphotropic virus 1 (HTLV-1). Interleukin 2 receptor alpha (IL-2Rα) is expressed in the leukemic cells of smoldering/chronic ATL patients, leading to constitutive activation of the JAK/STAT pathway and spontaneous proliferation. The PI3K/Akt/mTOR pathway also plays a critical role in ATL cell survival and proliferation. We previously performed a high-throughput screen that demonstrated additive/synergistic activity of Ruxolitinib, a JAK1/2 inhibitor, with AZD8055, an mTORC1/C2 inhibitor. However, effects of unintended JAK2 inhibition with Ruxolitinib limits it therapeutic potential for ATL patients, which lead us to evaluate a JAK1-specific inhibitor. Here, we demonstrated that Upadacitinib, a JAK-1 inhibitor, inhibited the proliferation of cytokine-dependent ATL cell lines and the expression of p-STAT5. Combinations of Upadacitinib with either AZD8055 or Sapanisertib, mTORC1/C2 inhibitors, showed anti-proliferative effects against cytokine-dependent ATL cell lines and synergistic effect with reducing tumor growth in NSG mice bearing IL-2 transgenic tumors. Importantly, the combination of these two agents inhibited ex vivo spontaneous proliferation of ATL cells from patients with smoldering/chronic ATL. Combined targeting of JAK/STAT and PI3K/Akt/mTOR pathways represents a promising therapeutic intervention for patients with smoldering/chronic ATL.

Keywords
Adult T cell leukemia; Combination therapy; JAK1 inhibitors; Smoldering/chronic ATL; mTOR inhibitors.
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