Introduction The membrane cytoskeletal crosslinker ezrin participates in several functions including cell adhesion, motility and cell survival, and there is increasing evidence that it regulates tumour progression. However, the role played by ezrin in breast cancer metastasis has not been clearly delineated.

Highlights d A large collection of HNSCC patient-derived xenograft models was established d ''Rapid'' engraftment of patient samples is highly prognostic d Genomic deregulation of the G1/S checkpoint pathway correlates with engraftment d CCND1 and CDKN2A genomic alterations are predictive of response to abemaciclib

The RET receptor tyrosine kinase has essential roles in cell survival, differentiation, and proliferation. Oncogenic activation of RET causes the cancer syndrome multiple endocrine neoplasia type 2 (MEN 2) and is a frequent event in sporadic thyroid carcinomas. However, the molecular mechanisms underlying RET's potent transforming and mitogenic signals are still not clear. Here, we show that nuclear localization of Bcatenin is frequent in both thyroid tumors and their metastases from MEN 2 patients, suggesting a novel mechanism of RET-mediated function through the B-catenin signaling pathway. We show that RET binds to, and tyrosine phosphorylates, B-catenin and show that the interaction between RET and B-catenin can be direct and independent of cytoplasmic kinases, such as SRC. As a result of RETmediated tyrosine phosphorylation, B-catenin escapes cytosolic down-regulation by the adenomatous polyposis coli/ Axin/glycogen synthase kinase-3 complex and accumulates in the nucleus, where it can stimulate B-catenin-specific transcriptional programs in a RET-dependent fashion. We show that down-regulation of B-catenin activity decreases RET-mediated cell proliferation, colony formation, and tumor growth in nude mice. Together, our data show that a Bcatenin-RET kinase pathway is a critical contributor to the development and metastasis of human thyroid carcinoma.

TRANSLATIONAL RELEVANCEHead and neck squamous cell carcinoma (HNSCC) is typically characterized by mutation of TP53 gene, associated to therapy resistance and high incidence of local recurrences. However, drugs specifically targeting mutant p53 proteins, frequently presenting gain-of-function activity associated with radioresistance, are not available. We then set out to identify mutant p53-associated functions that might be targeted with drugs currently used in HNSCC trials. This study identifies MYC as a crucial mediator of mutant p53 activity in HNSCC and PI3K inhibitors as compounds able to impinge on mutant p53-MYC dependent gene expression. Of note, down-regulation of mutant p53-MYC dependent genes is associated with response to PI3Kα-selective inhibitor Alpesilib (BYL719) in HNSCC.Research.