Small-molecule inhibitors that disrupt the MTDH–SND1 complex suppress breast cancer progression and metastasis

Abstract

Metastatic breast cancer is leading health burden worldwide. Previous studies have shown that Metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with Staphylococcal nuclease domain-containing 1 (SND1) which is required to sustain breast cancer progression in established tumors. We performed a small molecule compound screening to identify a class of specific inhibitors that disrupt the protein-protein interaction between MTDH-SND1, and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis, and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer. Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.

Mitochondrion-Localized SND1 Promotes Mitophagy and Liver Cancer Progression Through PGAM5

“…Cappellari et al found that SND1 regulates CD44 exon v5 splicing by forming a complex with SAM68 ( 43 ). More recently, SND1 has been found to interact with MTDH to form complexes ( 13 , 14 , 16 ). This complex binds and disrupts the stability of Tap1/2 mRNAs, which encode key components of the antigen-presentation machinery, thereby inhibiting tumor antigen presentation and T-cell activation, leading to immune evasion in triple-negative breast cancer ( 14 ).…”

“…Staphylococcal nuclease domain-containing protein 1 (SND1), also known as p100 or TSN, is an evolutionarily conserved protein that plays multifaceted roles by acting as a transcriptional coactivator ( 9 ) or is involved in the processing of precursor messenger RNA ( 10 ), miRNA decay ( 11 ), and ubiquitination and degradation ( 12 ) through localization to the cytoplasm and nucleus during tumorigenesis. Recently, SND1 was reported to play essential roles in breast cancer metastasis ( 13 , 14 ); however, whether SND1 localizes to mitochondria and regulates cell proliferation and tumor progression through mitochondrial-related functions is largely unknown.…”

“…SND1 is a substrate for caspase-3 during apoptosis and is a conserved component of the programmed cell death pathway ( 15 ). Wan et al found that disruption of the metadherin (MTDH)-SND1 complex sensitizes breast cancer cells to replication stress-induced apoptosis ( 16 , 17 ), and Shen et al demonstrated that disruption of the MTDH-SND1 complex by small-molecule inhibitors or compounds enhances the sensitivity of cancer cells to anti-programmed cell death protein 1 therapy, thus suppressing breast cancer progression and metastasis ( 13 , 14 ), but it remains unclear whether SND1 regulates mitophagy. Mitophagy, the selective degradation of dysfunctional or damaged mitochondria under stresses such as nutrient limitation, hypoxia, and chemical inducers, is a sophisticated system conserved from yeast to human that regulates mitochondrial quality and participates in quantity control to maintain mitochondrial fitness.…”

Pharmacological disruption of the MTDH–SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer

“…Several studies have implicated MTDH in promoting tumor growth and chemoresistance through association with Staphylococcal nuclease domain-containing 1 (SND1) 8 – 10 . Based on the small hydrophobic interaction interface between MTDH and SND1 revealed by crystal structure analysis 11 , our recent study identified a class of small chemical inhibitors that could specifically disrupt the complex (see companion manuscript 12 ). MTDH-SND1 inhibition by these compounds significantly reduces breast cancer progression and metastasis, and sensitizes tumors to chemotherapy, supporting the therapeutic potential of this new class of inhibitors 12 .…”

Tackling metastasis

“…Switching gears from tumor dormancy to metastatic growth, two Nature Cancer studies by Kang and colleagues explore the anti-metastatic effects of pharmacologically targeting the interaction between metadherin (MTDH) and staphylococcal nuclease domain-containing 1 (SND1) 8,9 , a protein complex that is known to be involved in tumor initiation, metastasis and therapy resistance. In their first study, the authors characterize the pro-metastatic role of the MTDH-SND1 complex in more detail through the use of an inducible Mtdh-knockout mouse to demonstrate that loss of this interaction inhibits mammary tumor progression and metastasis 8 . Notably, they go on to identify a class of small chemical inhibitors that disrupt this protein-protein interaction in breast cancer cells and demonstrate that these compounds can inhibit tumor growth and metastasis and can sensitize tumor cells to chemotherapy.…”