Proteasome ubiquitin receptor PSMD4 is an amplification target in breast cancer and may predict sensitivity to PARPi.
Poly (ADP-ribose) polymerase 1 (PARP1) is an enzyme involved in DNA repair under investigation as a chemotherapeutic target. Current randomized phase three trials of PARPi in metastatic breast cancer are limited to patients with documented BRCA1/2 mutations and no biomarker of PARPi beyond BRCA status is available. In an effort to identify novel biomarkers for PARP inhibition, we created a cell line (HCC1187/TALRES) resistant to the PARP1 inhibitor talazoparib. Herein we show by array-CGH that HCC1187/TALRES has a selective loss of the proteasome ubiquitin receptor PSMD4 amplicon resulting in significant down-regulation of PSMD4. Conversely, we find that breast cancer cell lines that have copy number gain or amplification for PSMD4 are significantly more sensitive to talazoparib. Functional studies reveal that knock-down of PSMD4 in amplified breast cancer cells and loss of the PSMD4 amplicon result in knock-down of PARP1 protein. We show that PSMD4 is amplified and overexpressed in breast cancer and its overexpression correlates with poor survival. Knock-down of PSMD4 results in a significant decrease in cell growth. We provide evidence that PSMD4 is a proteasomal amplification target in breast cancer that PSMD4 amplification confers sensitivity to PARP inhibition, and that PSMD4 amplification is lost in the process of acquiring resistance to PARPi. Finally, this study shows not only that PSMD4 copy number correlates with PARPi sensitivity, but also, that it may be a better predictor of sensitivity to PARPi than BRCA1/2 mutation.
Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, 90095, California.
Marlena S
0000-0001-6800-687X
MS
Fejzo
Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, 90095, California.
Lee
L
Anderson
Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, 90095, California.
Hsiao-Wang
HW
Chen
Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, 90095, California.
Enrique
E
Guandique
Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, 90095, California.
Ondrej
O
Kalous
Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, 90095, California.
Dylan
D
Conklin
Division of Hematology-Oncology, Department of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, 90095, California.
Dennis J
DJ
Slamon
D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005784:Gene Amplification; D006801:Humans; D061986:MCF-7 Cells; D010793:Phthalazines / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D016601:RNA-Binding Proteins
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; C498506:PSMD4 protein, human; D010793:Phthalazines; D016601:RNA-Binding Proteins; C586365:talazoparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D046988:Proteasome Endopeptidase Complex