ABSTRACT
BACKGROUND: Systemic therapy for metastatic clear cell sarcoma (CCS) bearing EWSR1-CREB1/ATF1 fusions remains an unmet clinical need in children, adolescents, and young adults. METHODS: To identify key signaling pathway vulnerabilities in CCS, a multi-pronged approach was taken: (i) genomic and transcriptomic landscape analysis, (ii) integrated chemical biology interrogations, (iii) development of CREB1/ATF1 inhibitors, and (iv) antibody-drug conjugate testing (ADC). The first approach encompassed DNA exome and RNA deep sequencing of the largest human CCS cohort yet reported consisting of 47 patient tumor samples and 8 cell lines. RESULTS: Sequencing revealed recurrent mutations in cell cycle checkpoint, DNA double-strand break repair or DNA mismatch repair genes, with a correspondingly low to intermediate tumor mutational burden. DNA multi-copy gains with corresponding high RNA expression were observed in CCS tumor subsets. CCS cell lines responded to the HER3 ADC patritumab deruxtecan in a dose-dependent manner in vitro, with impaired long term cell viability. CONCLUSION: These studies of the genomic, transcriptomic and chemical biology landscape represent a resource 'atlas' for the field of CCS investigation and drug development. CHK inhibitors are identified as having potential relevance, CREB1 inhibitors non-dependence of CCS on CREB1 activity was established, and the potential utility of HER3 ADC being used in CCS is found.
Subject(s)
Sarcoma, Clear Cell , Child , Adolescent , Young Adult , Humans , Sarcoma, Clear Cell/genetics , Sarcoma, Clear Cell/metabolism , Sarcoma, Clear Cell/pathology , Transcriptome , Genomics , Base Sequence , RNA , Oncogene Proteins, Fusion/geneticsABSTRACT
Monte Carlo (MC) simulations of conformational changes and protonation of Glu-242, a key residue that shuttles protons in cytochrome c oxidase (CcO), are reported. Previous studies suggest that this residue may play a role of the valve of the enzyme proton pump. Here we examine how sensitive the results of simulations are to the computational method used. We applied both molecular mechanic (MM) and hybrid quantum mechanic:molecular mechanic (QM:MM) methods and find that the results are qualitatively different. The results indicate that the mechanism for proton gating in CcO is still an open issue.
