Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.

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Tytuł:: Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition.
Autorzy:: Blessing AM; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Santiago-O'Farrill JM; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Mao W; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Pang L; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Ning J; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Pak D; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Bollu LR; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Rask P; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Iles L; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Yang H; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Tran S; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Elmir E; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Bartholomeusz G; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Langley R; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Lu Z; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Bast RC Jr; Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Źródło:: Cancer [Cancer] 2020 Aug 01; Vol. 126 (15), pp. 3579-3592. Date of Electronic Publication: 2020 Jun 02.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: <2005- >: Hoboken, NJ : Wiley
Original Publication: New York [etc.] Published for the American Cancer Society by J. Wiley [etc.]
MeSH Terms:: Anaplastic Lymphoma Kinase/*genetics
Ovarian Neoplasms/*drug therapy
STAT3 Transcription Factor/*genetics
rho GTP-Binding Proteins/*genetics
Anaplastic Lymphoma Kinase/antagonists & inhibitors ; Animals ; Autophagy/drug effects ; Cell Line, Tumor ; Cell Lineage/genetics ; Cell Survival/genetics ; Crizotinib/pharmacology ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Expression Regulation, Neoplastic/drug effects ; Heterografts ; Humans ; Mice ; Ovarian Neoplasms/genetics ; Ovarian Neoplasms/pathology ; Protein Kinase Inhibitors/pharmacology ; RNA, Small Interfering/genetics ; RNA, Small Interfering/pharmacology ; Signal Transduction/drug effects
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Grant Information:: P30 CA016672 United States CA NCI NIH HHS; CFP Foundation; National Foundation for Cancer Research; UL1 TR003167 United States TR NCATS NIH HHS; Anne and Harry Zarrow Foundation; R01 CA135354 United States CA NCI NIH HHS; P50 CA 217685 MD Anderson SPORE in Ovarian Cancer NCI; P50 CA 83639 MD Anderson SPORE in Ovarian Cancer NCI; Mossy Foundation; Roberson Endowment; RP170067 CPRIT Research Training Program; P30CA016672 National Cancer Institute (NCI); P50 CA217685 United States CA NCI NIH HHS; Stuart and Gaye-Lynn Zarrow; P50 CA083639 United States CA NCI NIH HHS
Contributed Indexing:: Keywords: GTP-binding protein Di-Ras3 (DIRAS3); anaplastic lymphoma kinase (ALK); autophagy; crizotinib; dormancy; ovarian cancer
Substance Nomenclature:: 0 (DIRAS3 protein, human)
0 (Protein Kinase Inhibitors)
0 (RNA, Small Interfering)
0 (STAT3 Transcription Factor)
0 (STAT3 protein, human)
53AH36668S (Crizotinib)
EC 2.7.10.1 (ALK protein, human)
EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
EC 3.6.5.2 (rho GTP-Binding Proteins)
Entry Date(s):: Date Created: 20200603 Date Completed: 20210520 Latest Revision: 20210802
Update Code:: 20240104
PubMed Central ID:: PMC7384209
DOI:: 10.1002/cncr.32985
PMID:: 32484926
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Background: Poor outcomes for patients with ovarian cancer relate to dormant, drug-resistant cancer cells that survive after primary surgery and chemotherapy. Ovarian cancer (OvCa) cells persist in poorly vascularized scars on the peritoneal surface and depend on autophagy to survive nutrient deprivation. The authors have sought drugs that target autophagic cancer cells selectively to eliminate residual disease.
Methods: By using unbiased small-interfering RNA (siRNA) screens, the authors observed that knockdown of anaplastic lymphoma kinase (ALK) reduced the survival of autophagic OvCa cells. Small-molecule ALK inhibitors were evaluated for their selective toxicity against autophagic OvCa cell lines and xenografts. Autophagy was induced by reexpression of GTP-binding protein Di-Ras3 (DIRAS3) or serum starvation and was evaluated with Western blot analysis, fluorescence imaging, and transmission electron microscopy. Signaling pathways required for crizotinib-induced apoptosis of autophagic cells were explored with flow cytometric analysis, Western blot analysis, short-hairpin RNA knockdown of autophagic proteins, and small-molecule inhibitors of STAT3 and BCL-2.
Results: Induction of autophagy by reexpression of DIRAS3 or serum starvation in multiple OvCa cell lines significantly reduced the 50% inhibitory concentration of crizotinib and other ALK inhibitors. In 2 human OvCa xenograft models, the DIRAS3-expressing tumors treated with crizotinib had significantly decreased tumor burden and long-term survival in 67% to 79% of mice. Crizotinib treatment of autophagic cancer cells further enhanced autophagy and induced autophagy-mediated apoptosis by decreasing phosphorylated STAT3 and BCL-2 signaling.
Conclusions: Crizotinib may eliminate dormant, autophagic, drug-resistant OvCa cells that remain after conventional cytoreductive surgery and combination chemotherapy. A clinical trial of ALK inhibitors as maintenance therapy after second-look operations should be seriously considered.
(© 2020 American Cancer Society.)

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