Biology subjects

Felice, C.

Publications and source records attributed to Felice, C..

2 recordsLinked to original sources

bioRxiv2026

PTP1B supports survival and regulates CFL1 and HSP90a abundance in trastuzumab-resistant HER2-positive breast cancer.

Trastuzumab resistance limits the treatment of HER2-positive breast cancer. Here, we identify protein tyrosine phosphatase 1B (PTP1B) as a survival dependency in models of intrinsic and acquired trastuzumab resistance, including cells with endogenous ERBB2 kinase domain mutations (L755S and V777L), a patient-derived tumor organoid model, and orthotopic xenografts. PTP1B expression was elevated in multiple trastuzumab-resistant models, accompanied by increased PI3K-AKT and ERK signaling in several of these. The PTP1B inhibitor DPM-1003 suppressed growth of trastuzumab-resistant cells and organoids, inhibited xenograft progression, and induced apoptosis. Genetic ablation of PTP1B reduced growth and restored trastuzumab responsiveness in multiple resistance models, although JIMT1 cells remained resistant. Quantitative phosphoproteomics, phosphotyrosine immunoprecipitation, and substrate-trapping assays identified cofilin-1 (CFL1) and HSP90 as substrates of PTP1B. Loss of PTP1B increased their tyrosine phosphorylation, reduced their abundance, and increased their recovery in ubiquitin pull-downs. Proteasome inhibition restored substrate abundance, and PTP1B re-expression restored protein levels in PTP1B-null cells. These findings support a model in which PTP1B-dependent dephosphorylation limits turnover of the substrates CFL1 and HSP90. Genetic or pharmacological targeting of PTP1B suppressed survival-associated signaling and increased apoptotic markers. Together, these results identify PTP1B as a therapeutic vulnerability in trastuzumab-resistant HER2-positive breast cancer and implicate regulation of CFL1 and HSP90 abundance in the accompanying signaling response.

cancer biology↗

bioRxiv2026

Inhibition of protein tyrosine phosphatase PTP1B function ameliorates pathophysiological deficits in Rett Syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder in which current therapeutic strategies remain largely focused on providing symptomatic relief without addressing underlying disease mechanisms. In contrast, we have identified the protein tyrosine phosphatase PTP1B as a mechanism-based therapeutic target and evaluated a class of selective, allosteric small-molecule inhibitors in female murine models of RTT. We show that one of these compounds localizes to brain regions central to motor coordination and cardio-respiratory control, which are core domains of RTT pathology. Pharmacological inhibition of PTP1B produces robust and sustained improvement in multiple disease symptoms, including muscle weakness, motor and coordination deficits, and cardiac and respiratory dysfunction. Concordant results obtained with genetic ablation of PTP1B, with effects maintained for over one year, demonstrate that phenotypic rescue arises from on-target modulation of disease-relevant signaling. Mechanistically, PTP1B inhibition is known to normalize neurotrophic and metabolic pathways, including TRKB and insulin/leptin signaling, thereby restoring circuit-level function. These findings establish PTP1B as a clinically actionable, disease-modifying target and demonstrate that selective, allosteric inhibition of a protein tyrosine phosphatase can achieve durable therapeutic benefit in vivo. This work provides a strong rationale for the clinical evaluation of PTP1B inhibitors as a mechanism-based treatment strategy for RTT. One Sentence SummaryWe have validated inhibition of PTP1B as a mechanism-based therapeutic strategy that alleviates a wide range of symptoms in a mouse model of Rett syndrome.

neuroscience↗