TY - JOUR
T1 - A HUWE1 defect causes PARP inhibitor resistance by modulating the BRCA1-∆11q splice variant
AU - Pettitt, Stephen J.
AU - Shao, Nan
AU - Zatreanu, Diana
AU - Frankum, Jessica
AU - Bajrami, Ilirjana
AU - Brough, Rachel
AU - Krastev, Dragomir B.
AU - Roumeliotis, Theodoros I.
AU - Choudhary, Jyoti S.
AU - Lorenz, Sonja
AU - Rust, Alistair
AU - de Bono, Johann S.
AU - Yap, Timothy A.
AU - Tutt, Andrew N.J.
AU - Lord, Christopher J.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/9/1
Y1 - 2023/9/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41388-023-02782-8
DO - 10.1038/s41388-023-02782-8
M3 - Article
C2 - 37491606
AN - SCOPUS:85165685748
SN - 0950-9232
VL - 42
SP - 2701
EP - 2709
JO - Oncogene
JF - Oncogene
IS - 36
ER -