PMID- 35831271
OWN - NLM
STAT- MEDLINE
DCOM- 20220715
LR  - 20230119
IS  - 2041-4889 (Electronic)
VI  - 13
IP  - 7
DP  - 2022 Jul 12
TI  - Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces 
      autophagic cell death via inhibiting mTOR.
PG  - 603
LID - 10.1038/s41419-022-05039-6 [doi]
LID - 603
AB  - Autophagy is a biological process that maintains cellular homeostasis and 
      regulates the internal cellular environment. Hyperactivating autophagy to trigger 
      cell death has been a suggested therapeutic strategy for cancer treatment. 
      Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates 
      autophagy; therefore, using a structure-based virtual screen analysis, we 
      identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 
      (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 
      in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR 
      signaling, thereby inhibiting the downstream events associated with increased LC3 
      conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and 
      tumor xenografts. Lomitapide also significantly suppresses the growth and 
      viability along with elevated autophagy in patient-derived colorectal cancer 
      organoids. Furthermore, a combination of lomitapide and immune checkpoint 
      blocking antibodies synergistically inhibits tumor growth in murine MC38 or 
      B16-F10 preclinical syngeneic tumor models. These results elucidate the direct, 
      tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, 
      which complement the current immune checkpoint blockade. This study highlights 
      the potential repurposing of lomitapide as a new therapeutic option for cancer 
      treatment.
CI  - (c) 2022. The Author(s).
FAU - Lee, Boah
AU  - Lee B
AD  - Department of Bio and Brain Engineering, Korea Advanced Institute of Science and 
      Technology (KAIST), Daejeon, 34141, Korea.
AD  - Department of Biological Sciences, KAIST, Daejeon, 34141, Korea.
AD  - ERSTEQ co., Ltd, Daejeon, 34013, Korea.
FAU - Park, Seung Ju
AU  - Park SJ
AD  - Department of Biological Sciences, KAIST, Daejeon, 34141, Korea.
AD  - ERSTEQ co., Ltd, Daejeon, 34013, Korea.
FAU - Lee, Seulgi
AU  - Lee S
AD  - Department of Biological Sciences, KAIST, Daejeon, 34141, Korea.
AD  - ERSTEQ co., Ltd, Daejeon, 34013, Korea.
FAU - Lee, Jinwook
AU  - Lee J
AD  - Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon 
      University, College of Medicine, Incheon, 21999, Korea.
FAU - Lee, Eunbeol
AU  - Lee E
AD  - Department of Biological Sciences, KAIST, Daejeon, 34141, Korea.
FAU - Yoo, Eun-Seon
AU  - Yoo ES
AUID- ORCID: 0000-0002-2401-0620
AD  - Department of Biological Sciences, KAIST, Daejeon, 34141, Korea.
FAU - Chung, Won-Suk
AU  - Chung WS
AUID- ORCID: 0000-0003-1060-9007
AD  - Department of Biological Sciences, KAIST, Daejeon, 34141, Korea.
FAU - Sohn, Jong-Woo
AU  - Sohn JW
AUID- ORCID: 0000-0002-2840-4176
AD  - Department of Biological Sciences, KAIST, Daejeon, 34141, Korea.
FAU - Oh, Byung-Chul
AU  - Oh BC
AUID- ORCID: 0000-0002-4277-7083
AD  - Department of Physiology, Lee Gil Ya Cancer and Diabetes Institute, Gachon 
      University, College of Medicine, Incheon, 21999, Korea.
FAU - Kim, Seyun
AU  - Kim S
AUID- ORCID: 0000-0003-0110-9414
AD  - Department of Bio and Brain Engineering, Korea Advanced Institute of Science and 
      Technology (KAIST), Daejeon, 34141, Korea. seyunkim@kaist.ac.kr.
AD  - Department of Biological Sciences, KAIST, Daejeon, 34141, Korea. 
      seyunkim@kaist.ac.kr.
AD  - KAIST Institute for the BioCentury, KAIST, Daejeon, 34141, Korea. 
      seyunkim@kaist.ac.kr.
AD  - KAIST Stem Cell Center, KAIST, Daejeon, 34141, Korea. seyunkim@kaist.ac.kr.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220712
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Antineoplastic Agents)
RN  - 0 (BMS201038)
RN  - 0 (Benzimidazoles)
RN  - 97C5T2UQ7J (Cholesterol)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Animals
MH  - *Antineoplastic Agents/pharmacology
MH  - *Autophagic Cell Death
MH  - Autophagy
MH  - Benzimidazoles
MH  - Cholesterol/pharmacology
MH  - *Colorectal Neoplasms/drug therapy
MH  - Humans
MH  - Mechanistic Target of Rapamycin Complex 1/metabolism
MH  - Mice
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC9279289
COIS- B.L., S.J.P., and S.K. are listed on the patent entitled "Composition for 
      treating colorectal cancer comprising lomitapide thereof as an active ingredient" 
      (submission date: 21 February 2020; application number: 10-2020-0021549; country: 
      the Republic of Korea; issuing institution: Korea Advanced Institute of Science 
      and Technology). The remaining authors declare no competing interests.
EDAT- 2022/07/14 06:00
MHDA- 2022/07/16 06:00
PMCR- 2022/07/12
CRDT- 2022/07/13 23:12
PHST- 2021/10/12 00:00 [received]
PHST- 2022/06/27 00:00 [accepted]
PHST- 2022/06/16 00:00 [revised]
PHST- 2022/07/13 23:12 [entrez]
PHST- 2022/07/14 06:00 [pubmed]
PHST- 2022/07/16 06:00 [medline]
PHST- 2022/07/12 00:00 [pmc-release]
AID - 10.1038/s41419-022-05039-6 [pii]
AID - 5039 [pii]
AID - 10.1038/s41419-022-05039-6 [doi]
PST - epublish
SO  - Cell Death Dis. 2022 Jul 12;13(7):603. doi: 10.1038/s41419-022-05039-6.