التفاصيل البيبلوغرافية
| العنوان: |
Crizotinib enhances PARP inhibitor efficacy in ovarian cancer cells and xenograft models by inducing autophagy. |
| المؤلفون: |
Santiago-O'Farrill JM; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Blessing Bollu A; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Yang H; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Orellana V; The University of Texas MD Anderson Cancer Center, Houston, United States., Pina M; The University of Texas MD Anderson Cancer Center, Houston, TX, United States., Zhang X; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Liu J; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Bast RC; The University of Texas MD Anderson Cancer Center, Houston, Texas, United States., Lu Z; The University of Texas MD Anderson Cancer Center, Houston, TX, United States. |
| المصدر: |
Molecular cancer research : MCR [Mol Cancer Res] 2024 May 23. Date of Electronic Publication: 2024 May 23. |
| Publication Model: |
Ahead of Print |
| نوع المنشور: |
Journal Article |
| اللغة: |
English |
| بيانات الدورية: |
Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101150042 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3125 (Electronic) Linking ISSN: 15417786 NLM ISO Abbreviation: Mol Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: |
Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002- |
| مستخلص: |
Poly (ADP-ribose) polymerase inhibitors (PARPi) can encounter resistance through various mechanisms, limiting their effectiveness. Our recent research showed that PARPi alone can induce drug resistance by promoting autophagy. Moreover, our studies have revealed that anaplastic lymphoma kinase (ALK) plays a role in regulating the survival of ovarian cancer cells undergoing autophagy. Here, we explored whether the ALK-inhibitor crizotinib could enhance the efficacy of PARPi by targeting drug-induced autophagic ovarian cancer cell and xenograft models. Our investigation demonstrates that crizotinib enhances the anti-tumor activity of PARPi across multiple ovarian cancer cells. Combination therapy with crizotinib and olaparib reduced cell viability and clonogenic growth in two-olaparib resistant cell lines. More importantly, this effect was consistently observed in patient-derived organoids. Furthermore, combined treatment with crizotinib and olaparib led to tumor regression in human ovarian xenograft models. Mechanistically, the combination resulted in increased levels of reactive oxygen species (ROS), induced DNA damage, and decreased the phosphorylation of AKT, mTOR, and ULK-1, contributing to increased olaparib-induced autophagy and apoptosis. Notably, pharmacologic, or genetic inhibition or autophagy reduced the sensitivity of ovarian cancer cell lines to olaparib and crizotinib treatment, underscoring the role of autophagy in cell death. Blocking ROS mitigated olaparib/crizotinib-induced autophagy and cell death while restoring levels of phosphorylated AKT, mTOR and ULK-1. These findings suggest that crizotinib can improve the therapeutic efficacy of olaparib by enhancing autophagy. Implications: The combination of crizotinib and PARPi presents a promising strategy, that could provide a novel approach to enhance outcomes for patients with ovarian cancer. |
| تواريخ الأحداث: |
Date Created: 20240523 Latest Revision: 20240523 |
| رمز التحديث: |
20240523 |
| DOI: |
10.1158/1541-7786.MCR-23-0680 |
| PMID: |
38780897 |
| قاعدة البيانات: |
MEDLINE |
