Massimo Moro1, Elisa Caiola2, Monica Ganzinelli3, Elisabetta Zulato4, Eliana Rulli2, Mirko Marabese2, Giovanni Centonze1, Adele Busico5, Ugo Pastorino6, Filippo G de Braud3, Claudio Vernieri7, Michele Simbolo8, Emilio Bria9, Aldo Scarpa8, Stefano Indraccolo4, Massimo Broggini2, Gabriella Sozzi10, Marina Chiara Garassino3. 1. Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 2. IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy. 3. Thoracic Oncology, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 4. Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy. 5. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 6. Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. 7. Thoracic Oncology, Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy. 8. ARC-Net Research Centre and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy. 9. U.O.C. Oncologia Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy. 10. Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. Electronic address: gabriella.sozzi@istitutotumori.mi.it.
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.
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 NSCLCpatients 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 NSCLCpatient-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.
Authors: Magdalena Markowicz-Piasecka; Karol Sadowski; Johanna Huttunen; Joanna Sikora; Kristiina M Huttunen Journal: Int J Mol Sci Date: 2021-05-26 Impact factor: 5.923
Authors: Felix B Meyer; Sophie Goebel; Sonja B Spangel; Christiane Leovsky; Doerte Hoelzer; René Thierbach Journal: BMC Cancer Date: 2021-05-28 Impact factor: 4.430