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Uncovering the Potential of Phosphatidylinositol 3-Kinase Inhibitors in Cutaneous T-Cell Lymphoma: Insights from High-Throughput In Vitro Screenings

      We read with interest the article by
      • Wu C.H.
      • Yang C.Y.
      • Wang L.
      • Gao H.X.
      • Rakhshandehroo T.
      • Afghani S.
      • et al.
      Cutaneous T-cell lymphoma PDX drug screening platform identifies cooperation between inhibitions of PI3Kα/δ and HDAC.
      on combination inhibition of phosphatidylinositol 3-kinase (PI3K) and histone deacetylase using xenograft models derived from patients with cutaneous T-cell lymphoma (CTCL). We agree with
      • Wu C.H.
      • Yang C.Y.
      • Wang L.
      • Gao H.X.
      • Rakhshandehroo T.
      • Afghani S.
      • et al.
      Cutaneous T-cell lymphoma PDX drug screening platform identifies cooperation between inhibitions of PI3Kα/δ and HDAC.
      that the full potential to harness PI3K inhibitors for advanced CTCL lies in the exploration of novel combination therapies. In this paper, we share our relevant preclinical dataset suggesting that as single agents, PI3K inhibitors exhibited limited efficacy against CTCL with advanced stage. We provide data from eight samples derived from patients with Sézary syndrome (SS) and four established CTCL cell lines analyzed by our previously described high-throughput in vitro functional drug screening platform (
      • Cyrenne B.M.
      • Lewis J.M.
      • Weed J.G.
      • Carlson K.R.
      • Mirza F.N.
      • Foss F.M.
      • et al.
      Synergy of BCL2 and histone deacetylase inhibition against leukemic cells from cutaneous T-cell lymphoma patients.
      ;
      • Kim S.R.
      • Lewis J.M.
      • Cyrenne B.M.
      • Monico P.F.
      • Mirza F.N.
      • Carlson K.R.
      • et al.
      BET inhibition in advanced cutaneous T cell lymphoma is synergistically potentiated by BCL2 inhibition or HDAC inhibition.
      ;
      • Mirza F.N.
      • Yumeen S.
      • Lewis J.M.
      • King A.L.O.
      • Kim S.R.
      • Carlson K.R.
      • et al.
      Screening novel agent combinations to expedite CTCL therapeutic development.
      ;
      • Yumeen S.
      • Mirza F.N.
      • Lewis J.M.
      • King A.L.O.
      • Kim S.R.
      • Carlson K.R.
      • et al.
      JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL.
      ) featuring a broad panel of PI3K inhibitors and revealing inferior effects of this drug class to those of currently available agents. We also discuss the considerations for using CTCL-established cell lines to guide more sensitive preclinical modeling studies (
      • Mirza F.N.
      • Yumeen S.
      • Lewis J.M.
      • King A.L.O.
      • Kim S.R.
      • Carlson K.R.
      • et al.
      Screening novel agent combinations to expedite CTCL therapeutic development.
      ;
      • Yumeen S.
      • Mirza F.N.
      • Lewis J.M.
      • King A.L.O.
      • Kim S.R.
      • Carlson K.R.
      • et al.
      JAK inhibition synergistically potentiates BCL2, BET, HDAC, and proteasome inhibition in advanced CTCL.
      ).

      Abbreviations:

      CTCL (cutaneous T-cell lymphoma), IC50 (50% inhibitory concentration), PI3K (phosphatidylinositol 3-kinase), SS (Sézary syndrome)
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