TY - JOUR
T1 - Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress
AU - Liu, Xihui
AU - Viswanadhapalli, Suryavathi
AU - Kumar, Shourya
AU - Lee, Tae Kyung
AU - Moore, Andrew
AU - Ma, Shihong
AU - Chen, Liping
AU - Hsieh, Michael
AU - Li, Mengxing
AU - Sareddy, Gangadhara R.
AU - Parra, Karla
AU - Blatt, Eliot B.
AU - Reese, Tanner C.
AU - Zhao, Yuting
AU - Chang, Annabel
AU - Yan, Hui
AU - Xu, Zhenming
AU - Pratap, Uday P.
AU - Liu, Zexuan
AU - Roggero, Carlos M.
AU - Tan, Zhenqiu
AU - Weintraub, Susan T.
AU - Peng, Yan
AU - Tekmal, Rajeshwar R.
AU - Arteaga, Carlos L.
AU - Lippincott-Schwartz, Jennifer
AU - Vadlamudi, Ratna K.
AU - Ahn, Jung Mo
AU - Raj, Ganesh V.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/7
Y1 - 2022/7
N2 - Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. 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. 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. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. 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.
AB - Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. 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. 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. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. 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.
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U2 - 10.1038/s43018-022-00389-8
DO - 10.1038/s43018-022-00389-8
M3 - Article
C2 - 35654861
AN - SCOPUS:85131308793
SN - 2662-1347
VL - 3
SP - 866
EP - 884
JO - Nature Cancer
JF - Nature Cancer
IS - 7
ER -