Biology subjects

Robinson, W. A.

Publications and source records attributed to Robinson, W. A..

3 recordsLinked to original sources

bioRxiv2025

Targeting BRAF kinase fusions with pan-RAF and vertical MAPK inhibition

BRAF kinase fusions are a form of structural variation in the genome and are recurrent events in driver-negative melanomas. While BRAF fusions reproducibly conserve the kinase domain, there is genetic variability with 5 gene partners and specific BRAF breakpoints. We investigated how genetic diversity of BRAF kinase fusions affects dimeric signaling and ERK activation. We overexpressed BRAF fusions with 5 gene partners including AGK, ZKSCAN1, ARMC10, PPFIBP2, and TRIM24 and found fusion dependent signaling and inhibitor sensitivity. Despite the development of next generation RAF inhibitors, there was paradoxical ERK phosphorylation with multiple pan-RAF inhibitors, which was ameliorated in certain BRAF fusions with vertical RAF/MEK inhibition using trametinib and LY3009120. Collectively, we observed some fusion-dependent effects but also tumor growth suppression and resolution of paradoxical activation with vertical pathway inhibition.

cancer biology↗

bioRxiv2025

Profiling serum oxylipin metabolites across melanoma subtypes and immunotherapy responders

ObjectivesThis study investigates the relationship between serum oxylipin profiles and response to immune checkpoint inhibitor therapy in melanoma subtypes to identify potential metabolic biomarkers for treatment response. MethodsIn a retrospective cohort study, serum samples from 43 stage III and stage IV melanoma patients treated at the University of Colorado Hospital from 2010 to 2023 were analyzed via ultra-high-pressure liquid chromatography-mass spectrometry. Melanoma patients were treated anti-PD-1 monotherapy or combination immune checkpoint inhibitor therapy and response was assessed using RECIST 1.1 criteria. ResultsUsing mass spectroscopy, we determined global oxylipin metabolite profiles are largely uniform pre-and post-treatment across melanoma subtypes including cutaneous, acral, mucosal, and uveal melanoma. Across subtypes, 33 oxylipin metabolites were analyzed, with limited variation observed overall. Prostaglandin J2 was more abundant in rare melanoma subtypes including acral, mucosal, and uveal melanoma compared to cutaneous melanoma. ConclusionsDespite limited variation of serum oxylipin molecular species by subtype and response status, we observed significant differences in Prostaglandin J2 which could serve as a potential biomarker for immune checkpoint inhibitor therapy response in melanoma. However, further investigation is warranted to explore the role of oxylipins in immune response modulation.

cancer biology↗

bioRxiv2023

SASH1 interacts with TNKS2 and promotes human melanocyte stem cell maintenance

Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1S519N variant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1S519N was defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for SASH1s promotion of stem-like function. Further, the SASH1S519N variant is in a bona fide Tankyrase-binding motif, and SASH1S519N alters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population.

cell biology↗