Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper.

Crystal structure of a seven-coordinate manganese(II) complex with tris-(pyridin-2-ylmeth-yl)amine (TMPA).

Structural analysis of (acetato-κ2O,O')(methanol-κO)[tris-(pyridin-2-ylmeth-yl)amine-κ4N,N',N'',N''']manganese(II) tetraphenyl-borate, [Mn(C2H3O2)(C18H18N4)(CH3OH)](C24H20B) or [Mn(TMPA)(Ac)(CH3OH)]BPh4 [TMPA = tris-(pyridin-2-ylmeth-yl)amine, Ac = acetate, BPh4 = tetra-phenyl-borate] by single-crystal X-ray diffraction reveals a complex cation with tetra-dentate coordination of the tripodal TMPA ligand, bidentate coordination of the Ac ligand and monodentate coordination of the methanol ligand to a single MnII center, balanced in charge by the presence of a tetra-phenyl-borate anion. The MnII complex has a distorted penta-gonal-bipyramidal geometry, in which the central amine nitro-gen and two pyridyl N atoms of the TMPA ligand, and two oxygen atoms of the acetate ligand occupy positions in the penta-gonal plane, while the third pyridyl nitro-gen of TMPA and the oxygen from the methanol ligand occupy the axial positions. Within the complex, the acetate O atoms participate in weak C-H⋯O hydrogen-bonding inter-actions with neighboring pyridyl moieties. In the crystal, complexes form dimers by pairs of O-H⋯O hydrogen bonds between the coordinated methanol of one complex and an acetate oxygen of the other, and weak π-stacking inter-actions between pyridine rings. Separate dimers then undergo additional π-stacking inter-actions between the pyridine rings of one moiety and either the pyridine or phenyl rings of another moiety that further stabilize the crystal.