![]() ![]() We previously identified oligobenzamides D2 and ERX-11 that bind to androgen receptor 4 and estrogen receptor (ER-α) 5, respectively. Despite advances in tumor characterization, the molecular heterogeneity of TNBC and subtype-specific differences in immune cell composition and genetic and pharmacologic vulnerabilities limit the activity of individual targeted therapies. However, TNBC represents a collection of multiple, biologically distinct subtypes categorized by their transcriptional profiles as basal-like (BL1, BL2), mesenchymal (M) or luminal androgen receptor (LAR) subtypes. There is thus an urgent and unmet need for effective targeted therapies in TNBC.Īn ideal targeted therapy exploits specific vulnerabilities in cancer cells that are not seen in normal cells. TNBCs are aggressive tumors and have the highest mortality rate among all BC subtypes: 150,000 deaths worldwide were attributed to metastatic TNBC in 2018 alone 2, 3. Currently, chemotherapy is the primary treatment option for the majority of patients with TNBC. The absence of expression of these receptors means that effective agents targeting these receptors will have no therapeutic activity in TNBC. Triple-negative breast cancers are negative for the expression of ER-α, PR or HER2, accounting for ~15% of new breast cancer (BC) diagnoses 1. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. ![]() Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. ![]() Nature Cancer volume 3, pages 866–884 ( 2022) Cite this article Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress ![]()
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