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Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC.
- Source :
-
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2018 Nov; Vol. 13 (11), pp. 1692-1704. Date of Electronic Publication: 2018 Aug 24. - Publication Year :
- 2018
-
Abstract
- Introduction: We hypothesized that activating KRAS mutations and inactivation of the liver kinase B1 (LKB1) oncosuppressor can cooperate to sustain NSCLC aggressiveness. We also hypothesized that the growth advantage of KRAS/LKB1 co-mutated tumors could be balanced by higher sensitivity to metabolic stress conditions, such as metformin treatment, thus revealing new strategies to target this aggressive NSCLC subtype.<br />Methods: We retrospectively determined the frequency and prognostic value of KRAS/LKB1 co-mutations in tissue specimens from NSCLC patients enrolled in the TAILOR trial. We generated stable LKB1 knockdown and LKB1-overexpressing isogenic H1299 and A549 cell variants, respectively, to test the in vitro efficacy of metformin. We also investigated the effect of metformin on cisplatin-resistant CD133 <superscript>+</superscript> cells in NSCLC patient-derived xenografts.<br />Results: We found a trend towards worse overall survival in patients with KRAS/LKB1 co-mutated tumors as compared to KRAS-mutated ones (hazard ratio: 2.02, 95% confidence interval: 0.94-4.35, p = 0.072). In preclinical experiments, metformin produced pro-apoptotic effects and enhanced cisplatin anticancer activity specifically in KRAS/LKB1 co-mutated patient-derived xenografts. Moreover, metformin prevented the development of acquired tumor resistance to 5 consecutive cycles of cisplatin treatment (75% response rate with metformin-cisplatin as compared to 0% response rate with cisplatin), while reducing CD133 <superscript>+</superscript> cells.<br />Conclusions: LKB1 mutations, especially when combined with KRAS mutations, may define a specific and more aggressive NSCLC subtype. Metformin synergizes with cisplatin against KRAS/LKB1 co-mutated tumors, and may prevent or delay the onset of resistance to cisplatin by targeting CD133 <superscript>+</superscript> cancer stem cells. This study lays the foundations for combining metformin with standard platinum-based chemotherapy in the treatment of KRAS/LKB1 co-mutated NSCLC.<br /> (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- AMP-Activated Protein Kinase Kinases
Aged
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Apoptosis drug effects
Carcinoma, Non-Small-Cell Lung enzymology
Carcinoma, Non-Small-Cell Lung genetics
Carcinoma, Non-Small-Cell Lung pathology
Cisplatin administration & dosage
Drug Synergism
Female
Humans
Lung Neoplasms enzymology
Lung Neoplasms genetics
Lung Neoplasms pathology
Male
Metformin administration & dosage
Middle Aged
Retrospective Studies
Antineoplastic Combined Chemotherapy Protocols pharmacology
Carcinoma, Non-Small-Cell Lung drug therapy
Cisplatin pharmacology
Lung Neoplasms drug therapy
Metformin pharmacology
Protein Serine-Threonine Kinases genetics
Proto-Oncogene Proteins p21(ras) genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1556-1380
- Volume :
- 13
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer
- Publication Type :
- Academic Journal
- Accession number :
- 30149143
- Full Text :
- https://doi.org/10.1016/j.jtho.2018.07.102