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Elimination of dormant, autophagic ovarian cancer cells and xenografts through enhanced sensitivity to anaplastic lymphoma kinase inhibition
Author(s) -
Blessing Alicia M.,
SantiagoO'Farrill Janice M.,
Mao Weiqun,
Pang Lan,
Ning Jing,
Pak Daewoo,
Bollu Lakshmi Reddy,
Rask Philip,
Iles LaKesla,
Yang Hailing,
Tran Samantha,
Elmir Ezzeddine,
Bartholomeusz Geoffrey,
Langley Robert,
Lu Zhen,
Bast Robert C.
Publication year - 2020
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.32985
Subject(s) - autophagy , crizotinib , cancer research , small interfering rna , cancer cell , programmed cell death , ovarian cancer , medicine , apoptosis , anaplastic lymphoma kinase , gene knockdown , cancer , biology , cell culture , pathology , transfection , lung cancer , biochemistry , genetics , malignant pleural effusion
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.