A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant.
Date
2023-09-01ICR Author
Author
Pettitt, SJ
Shao, N
Zatreanu, D
Frankum, J
Bajrami, I
Brough, R
Krastev, DB
Roumeliotis, TI
Choudhary, JS
Lorenz, S
Rust, A
de Bono, JS
Yap, TA
Tutt, ANJ
Lord, CJ
Type
Journal Article
Metadata
Show full item recordAbstract
Although PARP inhibitors (PARPi) now form part of the standard-of-care for the treatment of homologous recombination defective cancers, de novo and acquired resistance limits their overall effectiveness. Previously, overexpression of the BRCA1-∆11q splice variant has been shown to cause PARPi resistance. How cancer cells achieve increased BRCA1-∆11q expression has remained unclear. Using isogenic cells with different BRCA1 mutations, we show that reduction in HUWE1 leads to increased levels of BRCA1-∆11q and PARPi resistance. This effect is specific to cells able to express BRCA1-∆11q (e.g. BRCA1 exon 11 mutant cells) and is not seen in BRCA1 mutants that cannot express BRCA1-∆11q, nor in BRCA2 mutant cells. As well as increasing levels of BRCA1-∆11q protein in exon 11 mutant cells, HUWE1 silencing also restores RAD51 nuclear foci and platinum salt resistance. HUWE1 catalytic domain mutations were also seen in a case of PARPi resistant, BRCA1 exon 11 mutant, high grade serous ovarian cancer. These results suggest how elevated levels of BRCA1-∆11q and PARPi resistance can be achieved, identify HUWE1 as a candidate biomarker of PARPi resistance for assessment in future clinical trials and illustrate how some PARPi resistance mechanisms may only operate in patients with particular BRCA1 mutations.
Collections
Subject
Humans
Female
Poly(ADP-ribose) Polymerase Inhibitors
Drug Resistance, Neoplasm
Antineoplastic Agents
BRCA1 Protein
BRCA2 Protein
Mutation
Neoplasms
Ovarian Neoplasms
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases
Research team
Gene Function
Functional Proteomics
Prote & Metabolomics Fac
PrCa Targeted Therapy
Directorate Breast Canc
Language
eng
Date accepted
2023-07-12
License start date
2023-09-01
Citation
Oncogene, 2023, 42 (36), pp. 2701 - 2709
Publisher
SPRINGERNATURE