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

doi:10.1016/j.jtho.2018.07.102

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

IRCCS Fondazione Policlinico Universitario A. Gemelli

Research output: Contribution to journal › Article › peer-review

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
Pages (from-to)	1692-1704
Number of pages	13
Journal	Journal of Thoracic Oncology
Volume	13
Issue number	11
DOIs	https://doi.org/10.1016/j.jtho.2018.07.102
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

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10.1016/j.jtho.2018.07.102

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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

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

In: Journal of Thoracic Oncology, Vol. 13, No. 11, 2018, p. 1692-1704.

Research output: Contribution to journal › Article › peer-review

Moro, M, Caiola, E, Ganzinelli, M, Zulato, E, Rulli, E, Marabese, M, Centonze, G, Busico, A, Pastorino, U, de Braud, FG, Vernieri, C, Simbolo, M, Bria, E, Scarpa, A, Indraccolo, S, Broggini, M, Sozzi, G & Garassino, MC 2018, 'Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC', Journal of Thoracic Oncology, vol. 13, no. 11, pp. 1692-1704. https://doi.org/10.1016/j.jtho.2018.07.102

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. / Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC. In: Journal of Thoracic Oncology. 2018 ; Vol. 13, No. 11. pp. 1692-1704.

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

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. {\textcopyright} 2018 International Association for the Study of Lung Cancer",

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

note = "cited By 1",

year = "2018",

doi = "10.1016/j.jtho.2018.07.102",

language = "English",

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pages = "1692--1704",

journal = "Journal of Thoracic Oncology",

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TY - JOUR

T1 - Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC

AU - Moro, M.

AU - Caiola, E.

AU - Ganzinelli, M.

AU - Zulato, E.

AU - Rulli, E.

AU - Marabese, M.

AU - Centonze, G.

AU - Busico, A.

AU - Pastorino, U.

AU - de Braud, F.G.

AU - Vernieri, C.

AU - Simbolo, M.

AU - Bria, E.

AU - Scarpa, A.

AU - Indraccolo, S.

AU - Broggini, M.

AU - Sozzi, G.

AU - Garassino, M.C.

N1 - cited By 1

PY - 2018

Y1 - 2018

N2 - 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

AB - 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

KW - cisplatin

KW - metformin, A-549 cell line

KW - adult

KW - antineoplastic activity

KW - apoptosis

KW - Article

KW - cancer stem cell

KW - cohort analysis

KW - confidence interval

KW - controlled study

KW - DNA damage

KW - drug potentiation

KW - drug resistance

KW - female

KW - gene

KW - gene knockdown

KW - gene mutation

KW - hazard ratio

KW - human

KW - human cell

KW - intermethod comparison

KW - KRAS gene

KW - LKB1 gene

KW - major clinical study

KW - male

KW - metabolic stress

KW - NCI-H1299 cell line

KW - non small cell lung cancer

KW - priority journal

KW - retrospective study

KW - sensitivity analysis

KW - xenograft

U2 - 10.1016/j.jtho.2018.07.102

DO - 10.1016/j.jtho.2018.07.102

M3 - Article

VL - 13

SP - 1692

EP - 1704

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

IS - 11

ER -

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

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Keywords

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