FBXW7 deletion

We conclude that selective deletion of E3 ubiquitin ligase FBW7 in VE-cadherin positive endothelial cells instigates diffuse large B-cell lymphoma via upregulation of BCL6 stability. In addition, the mice with endothelial cell-specific deletion of Fbw7 provide a valuable preclinical platform for in vivo development and evaluation of novel therapeutic interventions for the treatment of DLBCL.

Therefore, in this review, we focused on FBXW7's role in a range of breast cancer malignant behaviors and summarized the pertinent cellular targets, signaling pathways, as well as the mechanisms regulating FBXW7 expression. We also proposed novel perspectives for the exploitation of alternative therapies and specific tumor markers for breast cancer by therapeutic strategies aiming at FBXW7.

Our data suggest that patients with WNT-MB carrying TP53 mutations or OTX2 gains (58.1%) are at higher risk of relapse. Eligibility of these patients for therapy de-escalation trials needs to be debated.

Computational analysis revealed significant deviation in stability and structural configuration of mutants R505L, R465H, R465P, R505G, R505C, R465C, R505S and R505L structures. Protein-protein interaction network of FBXW7 populated with promising hub proteins NOTCH1, c-Myc, CCNE1, STYX, KLG5, SREB1, NFKB2, SKP1 and CUL1; thus, alteration in the FBXW7 leads to aberration in their signalling pathways as well as their substrate binding ability makes this protein as attractive target for personalized therapeutic intervention.

In vitro and in vivo, loss of FBXW7 dramatically enhanced the efficacy of radiation treatment in IDH1 mutant cancer cells. Taken together, this work identifies FBXW7 deficiency as a potential biomarker representing both DNA repair and metabolic vulnerabilities that sensitizes IDH1 mutant cancers to radiotherapy.

P1, N=60, Repare Therapeutics

Adult pleomorphic uRMSs harbor TP53 mutations and high levels of copy number alterations. Our findings underscore the challenge in discriminating between uRMS and UCS with rhabdomyosarcomatous differentiation.

Our results demonstrate that the loss of Fbxw7 promotes the acquisition of Trp53 mutations and that the two cooperate in breast tumor development. Targeting c-Myc, E2F, or p53 may therefore be a beneficial treatment strategy for FBXW7-altered breast cancer patients.