Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC

M. Moro, E. Caiola, M. Ganzinelli, E. Zulato, E. Rulli, M. Marabese, G. Centonze, A. Busico, U. Pastorino, F.G. de Braud, C. Vernieri, M. Simbolo, E. Bria, A. Scarpa, S. Indraccolo, M. Broggini, G. Sozzi, M.C. Garassino

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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 languageEnglish
Pages (from-to)1692-1704
Number of pages13
JournalJournal of Thoracic Oncology
Volume13
Issue number11
DOIs
Publication statusPublished - 2018

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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

Cite this

Moro, M., Caiola, E., Ganzinelli, M., Zulato, E., Rulli, E., Marabese, M., Centonze, G., Busico, A., Pastorino, U., de Braud, F. G., Vernieri, C., Simbolo, M., Bria, E., Scarpa, A., Indraccolo, S., Broggini, M., Sozzi, G., & Garassino, M. C. (2018). Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC. Journal of Thoracic Oncology, 13(11), 1692-1704. https://doi.org/10.1016/j.jtho.2018.07.102