Discovery of molecularly-informed therapeutic strategies for mature T-cell leukemias and lymphomas.

Mature T-cell leukemias and lymphomas (mTCL) comprise a clinically and genetically heterogeneous group of lymphoid malignancies. Most subtypes of peripheral T-cell lymphomas and leukemic T-cell malignancies show an aggressive clinical course and poor prognosis. Thus, these diseases urgently require novel therapeutic strategies. Taking advantage of recent progress deciphering the genetic basis of mTCL, we generated a comprehensive database of genetic alterations from 1825 patients with mTCL and utilized bioinformatic methodology developed to support treatment decisions in molecular tumor boards to identify novel potential therapeutics. Based on the results of this approach, we performed a systematic in vitro drug screen in molecularly characterized cell lines of mTCL to assess the activity of potential therapeutics. Of these, the cell cycle regulator WEE1 stood out as a novel therapeutic target in a genetically defined subgroup of mTCL. Indeed, WEE1 kinase inhibitors potently induced replication stress, premature mitotic entry, accumulation of DNA damage and induction of apoptosis in mTCL cell lines. Building on the single-agent activity of clinical grade WEE1 inhibitors, we next explored potential drug combination strategies through mechanistic studies. With this, we identified strong synergistic effects of combined WEE1 and JAK inhibition in genetically defined subtypes of mTCL, including primary patient samples of T-cell prolymphocytic leukemia. In summary, our study provides a comprehensive overview of the genetic landscape in mTCL and potential therapeutics in genetically defined subtypes. As such, we identified synergistic effects of dual WEE1 and JAK inhibition in cases with altered JAK/STAT signaling as a blueprint for clinical testing.