Fig. 4: Development of PARPi-refractory disease in a patient with HUWE1 mutations.
From: A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant
A Schematic of patient treatment journey and biopsies analysed. B No evidence of BRCA1 reversion across all the patient biopsies. No secondary mutations were called using standard somatic variant calling or by manual inspection in IGV (Integrated Genomics Viewer; view around pathogenic mutation shown). C Two missense HUWE1 mutations in cis identified only in the post-PARPi tumour biopsy (G4253A;I4257T). Alignments for reads at the mutation site in HUWE1 are shown. D Mutations affect catalytic domain but not catalytic site directly. Structure of the HUWE1 catalytic HECT domain [57] (PDB:6XZ1) showing residues affected by mutations (pink) in relation to the catalytic cysteine reside (orange).
