The research objectives of the Unit “Cellular Networks and Molecular Therapeutic Targets” are pursued through the integrated experimental work of the following groups:

Falcioni’s group actively contributes to the identification of the molecular mechanisms responsible for the resistance to therapy with T-DM1 in Breast Cancer and Dabrafenib in BRAF-mutant melanoma and to the identification of novel therapeutic targets in both tumors. In the first case, this group discovered that adjuvant therapy with combo trastumab/pertuzumab induces translocation of HER2 to the nucleus, making this receptor no longer available for T-DM1 administrated in second line treatment. In the second case, the group found that Semaphorine6A, strongly expressed in BRAF-mutated melanoma, is a crucial mediator of tumor/stroma interactions involved in the resistance to MAPK inhibition.

Paggi’s group actively contributes to drug repurposing in the treatment of GB. Intelligent and rational drug repurposing or repositioning are possible strategies to develop new therapies implicating lower risks, shorter timelines to bedside and lower costs. To this end, we employ cell biology and proteomic platforms, as reverse-phase protein arrays (RPPA), activity-based protein profiling (ABPP), SeaHorse and confocal microscopy, to delve into pharmacodynamic characteristics of old drugs amenable of repositioning in the therapy of GB. In addition, this group was proficient in attributing to the kinase inhibitor SI113 the correct mechanism of action in inhibiting the PI3K/mTOR pathway and epithelial-to-mesenchymal transition, as well as in stimulating autophagy.

D’Orazi’s group is actively investigating the mechanisms of induced chemoresistance, in particular in solid cancers such as GB, breast, colon, and pancreatic cancers and with respect of the HIPK2-p53 pathway and of mutant p53 modulation. Particular attention has been dedicated to 1 the contribution of overexpressed NRF2 (in hyperglycemia or following treatments with novel curcumin complexes) in tuning down the drug-induced cancer cell death by reducing p53 apoptotic activity and 2 the potential role of NRF2 as inhibitor of HIPK2 apoptotic activity; 2 the interplay between endoplasmic reticulum (ER) stress and autophagy in inducing mutant p53 degradation, as potential druggable molecular targets; 3 the use of phenylbutyrate (PBA), already approved by FDA for the treatment of urea cycle disorders, as strong cytotoxic anticancer agent preferentially in mutant p53-carrying cancer cells, leading to mutant p53 degradation and downregulation of mutant p53-regulated pathways such as the mevalonate pathway. These findings highlight the role of NRF2 as potential biomarker of tumor response to therapies and underscore the key outcome of mutant p53 degradation to restore cancer cell sensitivity to anticancer drugs.

Soddu’s group is actively pursuing the molecular characterization of mitosis and cytokinesis functions of proteins usually involved in the DNA damage response, such as p53, HIPK2, and histone H2B. Particular attention has been dedicated to the contribution of centrosomal p53 in the mitotic surveillance pathway; the role of extrachromosomal histone H2B in abscission; the identification and characterization of a new HIPK2 isoform with a cytokinesis-specific function.