Discovery of molecularly-informed therapeutic strategies for mature T-cell neoplasms

Abstract Mature T-cell lymphomas and leukemias (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 >1 800 patients with mTCL and utilized bioinformatic methodology developed to support treatment decisions in molecular tumorboards to identify novel potential therapeutics. To assess the in vitro activity of potential therapeutics, broad drug screening was performed in molecularly characterized cell lines of mTCL. Notably, the cell cycle regulator WEE1 was identified as a novel therapeutic target in mTCL. Indeed, WEE1 kinase inhibitors potently induced replication stress, premature mitotic entry, accumulation of DNA damage and induction of apoptosis in mTCL cell lines. Exploring potential drug combination strategies through mechanistic studies, we identified strong synergistic effects of combined WEE1 and JAK inhibition in JAK/STAT driven preclinical models as well as in primary patient samples of T-cell prolymphocytic leukemia (T-PLL). In summary, our results identified combinatorial effects of WEE1 and JAK inhibition in genetically defined subtypes of mTCL.