Countering Breast Cancer's Counterpunch
Murray BW. Molecular Cancer Therapeutics October 2019.

Suppression of Nuclear Factor-κB by Glucocorticoid Receptor Blocks Estrogen-Induced Apoptosis in Estrogen-Deprived Breast Cancer Cells
Fan P…Jordan VC. Molecular Cancer Therapeutics October 2019.

The endoplasmic reticulum stress sensor PERK/NF-κB/TNFα axis has been identified to be critical for estrogen (E2)-induced apoptosis in long-term E2-deprived (LTED) breast cancer cells. Fan et al. found that both E2 and the synthetic glucocorticoid dexamethasone (Dex) upregulated inflammatory factors such as fatty acid desaturase 1 (FADS1) and interleukin-6 (IL-6). Unlike E2, Dex selectively and constantly suppressed TNFα expression. A mechanistic finding was that activated glucocorticoid receptor (GR) preferentially suppressed NF-κB DNA-binding activity, which prevented activation of NF-κB-dependent TNFα and ultimately resulted in complete blockade of E2-induced apoptosis. These findings have important clinical implications for the conservative therapeutic application of glucocorticoids in treatment of advanced aromatase inhibitor-resistant breast cancer.

High Proliferation Rate And A Compromised Spindle Assembly Checkpoint Confers Sensitivity To The MPS1 Inhibitor BOS172722 In Triple Negative Breast Cancers
Anderhub SJ…Linardopoulos S. Molecular Cancer Therapeutics October 2019.

BOS172722 is a highly potent, selective, and orally bioavailable MPS1 inhibitor currently in the clinic. BOS172722 treatment in combination with paclitaxel induces gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. MPS1 inhibition led to a significant sensitisation of TNBC cells to death and regression of patient-derived xenografts. The most important discovery in this paper from Anderhub et al. is that MPS1 inhibition induces significant cell killing, particularly in highly proliferative cancers. They anticipate that use of proliferation markers for patient selection may be beneficial for the success of MPS1 inhibitors in clinic.

Atovaquone: An Antiprotozoal Drug, Suppresses Primary And Resistant Breast Tumor Growth By Inhibiting HER2/β-catenin Signaling
Gupta N and Srivastava SK. Molecular Cancer Therapeutics October 2019.

Gupta et al. provide observable evidences to establish a strong antitumor effect of atovaquone, an anti-malarial drug in primary and paclitaxel-resistant breast cancer by inhibiting HER2/β-catenin signaling; overexpression of which is responsible for development of resistance to the current treatment regimen. Atovaquone at 30 mg/kg was highly efficacious in suppressing the growth of CI66, 4T1, and paclitaxel-resistant breast tumors. The projected human anti-cancer dose of atovaquone is 6 times less than the intended dose for malaria treatment, indicating that atovaquone is a highly safe and non-toxic drug that should be further pursued towards clinical development for the treatment of drug resistant breast cancer.

A Novel Anti-HER2 Antibody–Drug Conjugate XMT-1522 for HER2-Positive Breast and Gastric Cancers Resistant to Trastuzumab Emtansine
Le Joncour V…Barok M. Molecular Cancer Therapeutics October 2019.

Le Joncour and colleagues evaluated the biological activity of XMT-1522 (Mersana Therapeutics Inc.), a novel HER2-targeting antibody-drug conjugate in preclinical models of HER2-positive breast and gastric cancer. The authors found that XMT-1522 was more effective than T-DM1 (trastuzumab emtansine; Kadcyla) in HER2-positive breast and gastric cell lines sensitive to T-DM1, in addition, XMT-1522 was effective in cell lines resistant to T-DM1. In murine models, XMT-1522 eliminated breast and gastric cancer xenografts with primary or acquired resistance to T-DM1, and increased the survival. The results support the testing of XMT-1522 in clinical trials in patients with HER2-positive cancer.

Altered Steroid Milieu in AI-Resistant Breast Cancer Facilitates AR Mediated Gene-Expression Associated with Poor Response to Therapy
Creevey L…McIlroy M. Molecular Cancer Therapeutics October 2019.

Breast cancer resistance to aromatase inhibitor (AI) therapy affects ~30% of all patients. This study by Creevey et al. has identified androgen receptor (AR) mediated transcriptomic alterations arising from the altered steroid environment associated with AI therapy. SGK3 was validated as an androstenedione regulated transcript mediated by AR in collaboration with estrogen receptor (ER). Clinical relevance was evaluated in multiple cohorts and demonstrated that non-responders to AI therapy exhibit sustained expression of AR and SGK3 transcript. This highlights the importance of the steroid milieu, as alterations are likely to impact therapeutic response to endocrine therapy.

Targeting MUC1-C Inhibits TWIST1 Signaling in Triple-Negative Breast Cancer
Hata T…Kufe D. Molecular Cancer Therapeutics October 2019.

Cancer cell progression has been linked to EMT, stemness and drug resistance. Surprisingly, how these clinically important hallmarks of the cancer cell are interconnected has largely remained unclear. The present work by Hata et al. in triple-negative breast cancer (TNBC) provides new insights into the role of the MUC1-C oncoprotein in integrating the induction of TWIST1 and EMT with the CSC state and pleotropic drug resistance. Of clinical relevance, targeting MUC1-C results in the downregulation of EMT, suppression of stemness and reversal of the drug resistant phenotype. These findings indicate that MUC1-C is of importance in driving TNBC plasticity and dedifferentiation.

Co-targeting Bulk Tumor and CSCs in Clinically Translatable TNBC Patient-Derived Xenografts via Combination Nanotherapy
Sulaiman A…Wang L. Molecular Cancer Therapeutics October 2019.

Triple-negative breast cancer (TNBC) disproportionally accounts for the majority of breast cancer–related deaths throughout the world. This is mainly due to the lack of specific therapy capable of targeting both bulk tumor mass and cancer stem cells (CSC). In this study, Sulaiman et al. developed a nanotherapeutic approach to co-target both bulk tumor mass and CSCs by packaging conventional chemotherapeutic drug paclitaxel with FDA-approved photosensitizer verteporfin in a nanoparticle platform (PV-NP). The therapeutic efficacy of the PV-NP evaluated using a clinically relevant patient-derived xenograft model (PDX), which represents the heterogeneity and complexity of patients' primary tumors and is more accurate. The study showed that PV-NP significantly inhibited PDX tumor growth and prevented CSCs enrichment via co-suppressing CSC-associated signaling pathways.