Biology subjects

Faga, G.

Publications and source records attributed to Faga, G..

4 recordsLinked to original sources

bioRxiv2025

High-Throughput Screening Identifies PLK1 Inhibition as a Strategy to Potentiate BTK Blockade in Marginal Zone Lymphoma

B-cell receptor (BCR) signaling is a key therapeutic target in B-cell lymphomas, and Bruton tyrosine kinase inhibitors (BTKi) have demonstrated clinical efficacy in marginal zone lymphoma (MZL). However, the rate of complete remissions is relatively low, and resistance remains a significant clinical challenge, underscoring the need for novel combination strategies. To identify compounds that enhance the activity of BTKi and overcome resistance, we conducted a high-throughput screen of 1,695 compounds using a previously developed MZL model of acquired resistance to BTK and PI3K inhibitors derived from the Karpas1718 cell line. Thirty-three compounds showed single-agent anti-proliferative activity in the nanomolar range, both in the Karpas1718-resistant and parental cells. Based on their clinical potential in combination with BTKi, seven compounds were selected for further validation. The polo-like kinase 1 (PLK1) inhibitor rigosertib emerged as a top candidate, showing strong activity in both parental and BTKi-resistant cell lines. Combination treatment of rigosertib and BTKi zanubrutinib resulted in broad transcriptomic changes, characterized by the downregulation of pathways involved in B-cell activation, proliferation, and BCR signaling. Mechanistically, the combination reduced phosphorylation of key BCR pathway components and inhibited NF-{kappa}B nuclear translocation. These findings suggest that PLK1 inhibition can overcome BTKi resistance by further inhibiting BCR signaling through the canonical NF-{kappa}B pathway. Therefore, the dual pharmacological inhibition of BTK and PLK1 is a promising therapeutic approach for patients with MZL and warrants further preclinical and clinical investigations.

cancer biology↗

bioRxiv2025

The CRL7FBXW8 Complex Controls the Mammary Stem Cell Compartment Through Regulation of NUMB Levels

NUMB is a tumor suppressor gene that functions by inhibiting the action of the NOTCH proto-oncogene and enhancing the levels and activity of the tumor suppressor protein p53. In breast cancer (BC), NUMB loss-of-function (LOF), mediated by various molecular mechanisms, is a frequent and causal event. Herein, we establish that loss of NUMB protein, resulting from protein hyper-degradation, is the prevalent mechanism of NUMB LOF in BC. Through a RNAi-based screening, we identified the CRL7FBXW8 complex as the E3 ligase complex responsible for NUMB hyper-degradation in BC. Genetic and pharmacological inhibition of CRL7FBXW8 rescued the transformation-related phenotypes induced by NUMB LOF in BC cell lines and in patient-derived xenografts. These effects were directly dependent on the restoration of NUMB protein levels. Thus, enhanced CRL7FBXW8 activity, through its interference with the tumor suppressor activity of NUMB, is a causal alteration in BC, suggesting it as a potential therapeutic target for precision medicine.

cancer biology↗

bioRxiv2024

Adducins regulate morphology and fate of neural progenitors during neocortical neurogenesis

The evolutionary expansion of the mammalian neocortex is mediated by an increase in the proliferative capacity of neural progenitor cells. However, the molecular machinery controlling the proliferation of apical and basal progenitors during neocortical development is still poorly understood. Here we show that the three actin-associated morpho-regulatory adducins (ADD1-3), underlie abundance of basal progenitors in developing mouse and ferret neocortex in vivo and in human cortical organoids. Over expression of adducins in embryonic mouse neocortex increases the number of protrusions of basal progenitors, leading to an increase in their proliferative capacity and neuronal output. Conversely, knock-out of ADD1 in human cortical organoids, which also leads to down-regulation of other adducins, results in reduced proliferation of progenitors and aberrant neurogenesis. Hence, we show that adducins underlie proliferation and fate of neural progenitors, which are key cellular features underlying progression of mammalian neurogenesis.

neuroscience↗

bioRxiv2020

ATR expands embryonic stem cell fate potential in response to replication stress

Unrepaired DNA damage during embryonic development can be potentially inherited by a large population of cells. However, the quality control mechanisms that minimize the contribution of damaged cells to developing embryos remain poorly understood. Here, we uncovered an ATR- and CHK1-mediated transcriptional response to replication stress (RS) in ESCs that induces genes expressed in totipotent two-cell (2C) stage embryos and 2C-like cells. This response is mediated by Dux, a multicopy retrogene defining the cleavage-specific transcriptional program in placental mammals. In response to RS, DUX triggers the transcription of 2C-like markers such as murine endogenous retrovirus-like elements (MERVL) and Zscan4. This response can also be elicited by ETAA1-mediated ATR activation in the absence of RS. ATR-mediated activation of DUX requires GSRF1 dependent post-transcriptional regulation of Dux mRNA. Strikingly, activation of ATR expands ESCs fate potential by extending their contribution to both embryonic and extra{-}embryonic tissues. These findings define a novel ATR dependent pathway involved in maintaining genome stability in developing embryos by controlling ESCs fate in response to RS.

cell biology↗