Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC Massimo Moro, MSc, Elisa Caiola, PhD,

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Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC Massimo Moro, MSc, Elisa Caiola, PhD, Monica Ganzinelli, PhD, Elisabetta Zulato, PhD, Eliana Rulli, PhD, Mirko Marabese, PhD, Giovanni Centonze, MLT, Adele Busico, DSc, Ugo Pastorino, MD, Filippo G. de Braud, MD, Claudio Vernieri, MD, PhD, Michele Simbolo, PhD, Emilio Bria, MD, Aldo Scarpa, MD, Stefano Indraccolo, MD, Massimo Broggini, PhD, Gabriella Sozzi, PhD, Marina Chiara Garassino, MD Journal of Thoracic Oncology Volume 13, Issue 11, Pages 1692-1704 (November 2018) DOI: 10.1016/j.jtho.2018.07.102 Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 1 Kaplan Meier curves for progression-free survival (A) and overall survival (B) in KRASMUT/LKB1WT versus KRASMUT/LKB1MUT patients enrolled within the TAILOR trial. Hazard ratio: univariate (unadjusted) and multivariate (adjusted for ECOG-PS, sex, histotype, smoking history and treatment arm). WT, wild-type; LKB1, liver kinase B1; HR, hazard ratio; Chi2, chi squared; CI, confidence interval; ECOG-PS, Eastern Cooperative Oncology Group performance status. Journal of Thoracic Oncology 2018 13, 1692-1704DOI: (10.1016/j.jtho.2018.07.102) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 2 Effects of metformin on A549 (KRASG12S/LKB1del) and H1299 (KRASWT/LKB1WT) NSCLC cell line. (A) Dose-effect curve shows that both cell lines are affected by biguanide treatment in a similar way in terms of number of live cells after 24 hours of treatment. (B) Annexin V staining shows that 50 mmol/L metformin treatment for 24 hours induces a 10-fold increase and 7.6-fold increase of apoptosis induction in A549 and H1299 cells, respectively. These differences are exacerbated with 250 mmol/L metformin treatment for 24 hours where the biguanide induces a 46.2-fold increase and 18.5-fold increase in A549 and H1299 cells, respectively. *p < 0.05; **p < 0.01 compared to controls; #p < 0.05; ##p < 0.01 compared to 50 mM metformin. (C) Metformin increases apoptosis induced by cisplatin in A549 transfected with control plasmid (pBABE) but not in A549 cells with ectopic expression of wild-type LKB1 (LKB1WT) *p < 0.05; **p < 0.01; compared to untreated control. §§§p < 0.001 LKB1WTcompared to pBABE cells. ###p < 0.001 cisplatin-treated compared to cisplatin and metformin treated. (D) Metformin increases apoptosis induced by cisplatin treatment only in isogenic H1299 KRASG12C/LKB1del cell line. *p < 0.05; compared to control cells #p < 0.01; cisplatin-treated compared to cisplatin-and-metformin treated cells. pBABE, control plasmid; LKB1, liver kinase B1. Journal of Thoracic Oncology 2018 13, 1692-1704DOI: (10.1016/j.jtho.2018.07.102) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 3 In vivo treatments of PDX111 (KRASG12V/LKB1WT) and PDX73 (KRASG12V/LKB1K287X). (A) Metformin induces a slight decrease in tumor growth at 100 mg/kg daily dosage in PDX111, and has no effects on tumor growth at 100 mg/kg daily dosage in PDX73. (B) Immunohistochemistry analysis cleaved caspase 3 and Ki-67 expression of treated PDXs. Cleaved caspase 3 expression in PDX111 remains stable upon metformin treatments both at 100 mg/kg (average of 600 positive cells/quadrant) and at 800 mg/kg (750 positive cell/quadrant). On the contrary, Ki-67 expression gradually decreases with increasing metformin doses (920, 615, 550 positive cells/quadrant in untreated, 100 mg/kg and 800 mg/kg metformin-treated tumors, respectively). In the KRAS/LKB1 co-mutated PDX73, metformin induces an increase of apoptosis, as shown by a gradual increase in cleaved caspase 3 with increasing metformin dosage (80, 150, 750 positive cells/quadrant in untreated, 100 mg/kg and 800 mg/kg metformin-treated tumors, respectively); whereas Ki-67 expression remains at levels comparable with those of untreated tumors (950, 950, 1000 positive cells/quadrant in untreated, 100 mg/kg and 800 mg/kg metformin- treated tumors, respectively). Hematoxylin-eosin staining shows necrotic areas (highlighted with an asterisk [*]) only in double-mutated PDX73 upon metformin treatment. (C) Increasing metformin dosage to 800 mg/kg daily, a dose-dependent effect of biguanide treatment on PDX growth is appreciable only in KRAS/LKB1 co-mutated PDX73. (D) Metformin treatment (800 mg/kg) ameliorates cisplatin effects only in KRAS/LKB1 co-mutated PDX73, whereas no differences between metformin alone, cisplatin alone, or a combination of the two are appreciable in LKB1 wild-type PDX111. (E) Serial transplantation and serial treatment cycles of cisplatin or cisplatin and metformin combination in KRAS/LKB1 co-mutated PDX73. Cisplatin-treated tumors progressively become resistant to treatments, whereas effects of the combination of cisplatin and metformin last for 5 cycles with a progressive increase in the response rate (F). LKB1, liver kinase B1. Journal of Thoracic Oncology 2018 13, 1692-1704DOI: (10.1016/j.jtho.2018.07.102) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions

Figure 4 Fluorescence-activated cell sorting (FACS) analysis of tumor samples from KRAS/LKB1 co-mutated PDX73 tumors treated with cisplatin or cisplatin and metformin during the serial transplantation experiment. (A, B) CD133+ CSCs percentage increases at each passage in the cisplatin-treated tumors and this CSCs enrichment is counteracted in the cisplatin-and-metformin– treated tumors. In the last serial passage, when tumors became completely resistant to treatment, cisplatin effects are no more appreciable in terms of CSCs enrichment, whereas in the cisplatin-and-metformin–treated tumors a decrease of CSCs percentage is appreciable. (C) Tumors lag time (time tumors need to reach 150 mm3 volume after implant) gradually increases in cisplatin-and-metformin–treated tumors compared to both controls and cisplatin-treated tumors. (D) A similar effect on counteracting cisplatin-induced CSCs enrichment is appreciable also in KRASG12V/LKB1WT PDX111. LKB1, liver kinase B1. Journal of Thoracic Oncology 2018 13, 1692-1704DOI: (10.1016/j.jtho.2018.07.102) Copyright © 2018 International Association for the Study of Lung Cancer Terms and Conditions