Background The human proteasome gene family (PSM) consists of 49 genes that play a crucial role in cancer proteostasis. However, little is known about the effect of PSM gene expression and genetic alterations on clinical outcome in different cancer forms. Methods Here, we performed a comprehensive pan-cancer analysis of genetic alterations in PSM genes and the subsequent prognostic value of PSM expression using data from The Cancer Genome Atlas (TCGA) containing over 10,000 samples representing up to 33 different cancer types. External validation was performed using a breast cancer cohort and KM plotter with four cancer types. Results The PSM genetic alteration frequency was high in certain cancer types (e.g. 67%; esophageal adenocarcinoma), with DNA amplification being most common. Compared with normal tissue, most PSM genes were predominantly overexpressed in cancer. Survival analysis also established a relationship with PSM gene expression and adverse clinical outcome, where PSMA1 and PSMD11 expression were linked to more unfavorable prognosis in ≥ 30% of cancer types for both overall survival (OS) and relapse-free interval (PFI). Interestingly, PSMB5 gene expression was associated with OS (36%) and PFI (27%), and OS for PSMD2 (42%), especially when overexpressed. Conclusion These findings indicate that several PSM genes may potentially be prognostic biomarkers and novel therapeutic targets for different cancer forms.

Recombinant α1-microglobulin (A1M) is a proposed radioprotector during 177Lu-octreotate therapy of neuroendocrine tumors (NETs). To ensure a maintained therapeutic effect, we previously demonstrated that A1M does not affect the 177Lu-octreotate induced decrease in GOT1 tumor volume. However, the underlying biological events of these findings are still unknown. The aim of this work was to examine the regulation of apoptosis-related genes in GOT1 tumors short-time after i.v. administration of 177Lu-octreotate with and without A1M or A1M alone. Human GOT1 tumor-bearing mice received 30 MBq 177Lu-octreotate or 5 mg/kg A1M or co-treatment with both. Animals were sacrificed after 1 or 7 days. Gene expression analysis of apoptosis-related genes in GOT1 tissue was performed with RT-PCR. In general, similar expression patterns of pro- and anti-apoptotic genes were found after 177Lu-octreotate exposure with or without co-administration of A1M. The highest regulated genes in both irradiated groups compared to untreated controls were FAS and TNFSFRS10B. Administration of A1M alone only resulted in significantly regulated genes after 7 days. Co-administration of A1M did not negatively affect the transcriptional apoptotic response of 177Lu-octreotate in GOT1 tumors.

Background: The de novo drug development process is expensive and challenging, with a high risk of failure. Drug repurposing can ideally identify novel therapeutic indications for FDA-approved drugs with pre-existing pre-clinical and clinical evidence. Both aspirin and tamoxifen drugs are good examples of successful drug repurposing in oncology. Although proteasome inhibitors such as bortezomib and carfilzomib are currently only used to treat multiple myeloma and basal cell lymphoma, we and others have shown that triple-negative breast cancer (TNBC) is particularly sensitive to proteasome inhibition. TNBC is an aggressive form of breast cancer with an urgent need for novel treatment options. Here, we evaluate the potency of proteasome inhibitors and other clinically relevant chemotherapeutic agents on TNBC cell lines. Methods: We performed a high-throughput drug sensitivity screen with eight cell lines representing the four TNBC subtypes (basal-like 1: HCC70 and MDA-MB-468; basal-like 2: HCC1806 and MDA-MB-436; mesenchymal-like: BT-549 and HCC38; luminal androgen receptor: CAL-148 and MDA-MB-435) and MCF-7 as control (estrogen and progesterone receptor-positive) exposed to 18 drugs (11 proteasome inhibitors, 2 mitosis inhibitors, 2 topoisomerase inhibitors, and 3 platinum agents) for 24 hours. Drug potency was determined using the IC50, GR50, GRmax drug metrics. IDACombo was then used to predict efficacious drug combinations, followed by calculation of synergistic drug combinations with SynergyFinder. Results: TNBC cell lines were generally more sensitive to proteasome inhibitors with significantly reduced cell viability than clinically relevant drugs, e.g. paclitaxel. Although the potency of different proteasome inhibitors varied, the most potent proteasome inhibitors included bortezomib, carfilzomib, delanzomib, epoxomicin, and MLN-2238. According to the GR50 values, HCC38 (range, 8.2-382.7 nM) and MDA-MB-468 (range, 10.8-110.6 nM) were most sensitive to proteasome inhibition, whereas the least sensitive TNBC cell lines were HCC1806 (range, 289.9-Inf nM) and BT-549 (range, 101.0-Inf nM). Using the drug sensitivity screening results for single drugs, IDACombo predicted potent drug combinations for different combinations of bortezomib, carboplatin, carfilzomib, delanzomib, docetaxel, doxorubicin, epirubicin, epoxomicin, MLN-2238, MLN-9708, and nedaplatin. Conclusions: In summary, some proteasome inhibitors (e.g. bortezomib) had a substantial impact on TNBC cell survival. These findings indicate that proteasome inhibitors, together with other forms of chemotherapy, may be further explored as a novel complement treatment for TNBC. Citation Format: Peter Larsson, Daniella Pettersson, Maxim Olsson, Eva Forssell-Aronsson, Anikó Kovács, Per Karlsson, Khalil Helou, Toshima Z. Parris. Repurposing proteasome inhibitors for improved treatment of triple-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-17.