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. 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+ cells in NSCLC patient-derived xenografts. 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+ cells. 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+ 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. © 2018 International Association for the Study of Lung Cancer
Original language | English |
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Pages (from-to) | 1692-1704 |
Number of pages | 13 |
Journal | Journal of Thoracic Oncology |
Volume | 13 |
Issue number | 11 |
DOIs | |
Publication status | Published - 2018 |
Keywords
- cisplatin
- metformin, A-549 cell line
- adult
- antineoplastic activity
- apoptosis
- Article
- cancer stem cell
- cohort analysis
- confidence interval
- controlled study
- DNA damage
- drug potentiation
- drug resistance
- female
- gene
- gene knockdown
- gene mutation
- hazard ratio
- human
- human cell
- intermethod comparison
- KRAS gene
- LKB1 gene
- major clinical study
- male
- metabolic stress
- NCI-H1299 cell line
- non small cell lung cancer
- priority journal
- retrospective study
- sensitivity analysis
- xenograft