Caloric restriction and metformin selectively improved LKB1-mutated NSCLC tumor response to chemo- and chemo-immunotherapy.
Caloric restriction
Cancer metabolism
KRAS
LKB1
Metformin
NSCLC
Journal
Journal of experimental & clinical cancer research : CR
ISSN: 1756-9966
Titre abrégé: J Exp Clin Cancer Res
Pays: England
ID NLM: 8308647
Informations de publication
Date de publication:
02 Jan 2024
02 Jan 2024
Historique:
received:
07
09
2023
accepted:
11
12
2023
medline:
2
1
2024
pubmed:
2
1
2024
entrez:
2
1
2024
Statut:
epublish
Résumé
About 10% of NSCLCs are mutated in KRAS and impaired in STK11/LKB1, a genetic background associated with poor prognosis, caused by an increase in metastatic burden and resistance to standard therapy. LKB1 is a protein involved in a number of biological processes and is particularly important for its role in the regulation of cell metabolism. LKB1 alterations lead to protein loss that causes mitochondria and metabolic dysfunction that makes cells unable to respond to metabolic stress. Different studies have shown how it is possible to interfere with cancer metabolism using metformin and caloric restriction (CR) and both modify the tumor microenvironment (TME), stimulating the switch from "cold" to "hot". Given the poor therapeutic response of KRAS Mouse cell lines were derived from lung nodules of transgenic mice carrying KRAS Our preclinical results indicate that in NSCLC KRAS Our in vitro and in vivo preliminary studies confirm our hypothesis that the addition of metformin and CR is able to improve the antitumor activity of chemo and chemoimmunotherapy in LKB1 impaired tumors, exploiting their inability to overcome metabolic stress.
Sections du résumé
BACKGROUND
BACKGROUND
About 10% of NSCLCs are mutated in KRAS and impaired in STK11/LKB1, a genetic background associated with poor prognosis, caused by an increase in metastatic burden and resistance to standard therapy. LKB1 is a protein involved in a number of biological processes and is particularly important for its role in the regulation of cell metabolism. LKB1 alterations lead to protein loss that causes mitochondria and metabolic dysfunction that makes cells unable to respond to metabolic stress. Different studies have shown how it is possible to interfere with cancer metabolism using metformin and caloric restriction (CR) and both modify the tumor microenvironment (TME), stimulating the switch from "cold" to "hot". Given the poor therapeutic response of KRAS
METHODS
METHODS
Mouse cell lines were derived from lung nodules of transgenic mice carrying KRAS
RESULTS
RESULTS
Our preclinical results indicate that in NSCLC KRAS
CONCLUSION
CONCLUSIONS
Our in vitro and in vivo preliminary studies confirm our hypothesis that the addition of metformin and CR is able to improve the antitumor activity of chemo and chemoimmunotherapy in LKB1 impaired tumors, exploiting their inability to overcome metabolic stress.
Identifiants
pubmed: 38163906
doi: 10.1186/s13046-023-02933-5
pii: 10.1186/s13046-023-02933-5
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6Subventions
Organisme : Fondazione AIRC per la ricerca sul cancro ETS
ID : IG 2017-20085
Organisme : Fondazione AIRC per la ricerca sul cancro ETS
ID : IG 2020-24347
Informations de copyright
© 2023. The Author(s).
Références
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA A Cancer J Clin. 2021;71:209–49.
doi: 10.3322/caac.21660
Casal-Mouriño A, Ruano-Ravina A, Lorenzo-González M, Rodríguez-Martínez Á, Giraldo-Osorio A, Varela-Lema L, et al. Epidemiology of stage III lung cancer: frequency, diagnostic characteristics, and survival. Transl Lung Cancer Res. 2021;10:506–18.
pubmed: 33569332
pmcid: 7867742
doi: 10.21037/tlcr.2020.03.40
Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol. 2015;16:e165–72.
pubmed: 25846096
pmcid: 4470698
doi: 10.1016/S1470-2045(14)71180-5
Luo Y-H, Luo L, Wampfler JA, Wang Y, Liu D, Chen Y-M, et al. 5-year overall survival in patients with lung cancer eligible or ineligible for screening according to US Preventive Services Task Force criteria: a prospective, observational cohort study. Lancet Oncol. 2019;20:1098–108.
pubmed: 31255490
pmcid: 6669095
doi: 10.1016/S1470-2045(19)30329-8
Zhou C, Wu Y-L, Chen G, Feng J, Liu X-Q, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011;12:735–42.
pubmed: 21783417
doi: 10.1016/S1470-2045(11)70184-X
Mok TS, Wu Y-L, Ahn M-J, Garassino MC, Kim HR, Ramalingam SS, et al. Osimertinib or Platinum-Pemetrexed in EGFR T790M–Positive Lung Cancer. N Engl J Med. 2017;376:629–40.
pubmed: 27959700
doi: 10.1056/NEJMoa1612674
Soria J-C, Tan DSW, Chiari R, Wu Y-L, Paz-Ares L, Wolf J, et al. First-line ceritinib versus platinum-based chemotherapy in advanced ALK -rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study. The Lancet. 2017;389:917–29.
doi: 10.1016/S0140-6736(17)30123-X
Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823–33.
pubmed: 27718847
doi: 10.1056/NEJMoa1606774
Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. N Engl J Med. 2018;378:2078–92.
pubmed: 29658856
doi: 10.1056/NEJMoa1801005
Hong L, Negrao MV, Dibaj SS, Chen R, Reuben A, Bohac JM, et al. Programmed Death-Ligand 1 Heterogeneity and Its Impact on Benefit From Immune Checkpoint Inhibitors in NSCLC. J Thorac Oncol. 2020;15:1449–59.
pubmed: 32389639
doi: 10.1016/j.jtho.2020.04.026
Chen Z, Cheng K, Walton Z, Wang Y, Ebi H, Shimamura T, et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature. 2012;483:613–7.
pubmed: 22425996
pmcid: 3385933
doi: 10.1038/nature10937
Shackelford DB, Shaw RJ. The LKB1–AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9:563–75.
pubmed: 19629071
pmcid: 2756045
doi: 10.1038/nrc2676
Gill RK, Yang S-H, Meerzaman D, Mechanic LE, Bowman ED, Jeon H-S, et al. Frequent homozygous deletion of the LKB1/STK11 gene in non-small cell lung cancer. Oncogene. 2011;30:3784–91.
pubmed: 21532627
pmcid: 3616488
doi: 10.1038/onc.2011.98
Caiola E, Falcetta F, Giordano S, Marabese M, Garassino MC, Broggini M, et al. Co-occurring KRAS mutation/LKB1 loss in non-small cell lung cancer cells results in enhanced metabolic activity susceptible to caloric restriction: an in vitro integrated multilevel approach. J Exp Clin Cancer Res. 2018;37:302.
pubmed: 30514331
pmcid: 6280460
doi: 10.1186/s13046-018-0954-5
Skoulidis F, Goldberg ME, Greenawalt DM, Hellmann MD, Awad MM, Gainor JF, et al. STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma. Cancer Discov. 2018;8:822–35.
pubmed: 29773717
pmcid: 6030433
doi: 10.1158/2159-8290.CD-18-0099
Skoulidis F, Heymach JV. Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy. Nat Rev Cancer. 2019;19:495–509.
pubmed: 31406302
pmcid: 7043073
doi: 10.1038/s41568-019-0179-8
Skoulidis F, Arbour KC, Hellmann MD, Patil PD, Marmarelis ME, Awad MM, et al. Association of STK11/LKB1 genomic alterations with lack of benefit from the addition of pembrolizumab to platinum doublet chemotherapy in non-squamous non-small cell lung cancer. JCO. 2019;37:102–102.
doi: 10.1200/JCO.2019.37.15_suppl.102
Whang YM, Park SI, Trenary IA, Egnatchik RA, Fessel JP, Kaufman JM, et al. LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small-cell lung cancer (NSCLC) cells. Oncogene. 2016;35:856–66.
pubmed: 26119936
doi: 10.1038/onc.2015.140
Carretero J, Medina PP, Blanco R, Smit L, Tang M, Roncador G, et al. Dysfunctional AMPK activity, signalling through mTOR and survival in response to energetic stress in LKB1-deficient lung cancer. Oncogene. 2007;26:1616–25.
pubmed: 16953221
doi: 10.1038/sj.onc.1209951
Moro M, Caiola E, Ganzinelli M, Zulato E, Rulli E, Marabese M, et al. Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC. J Thorac Oncol. 2018;13:1692–704.
pubmed: 30149143
doi: 10.1016/j.jtho.2018.07.102
Borzi C, Ganzinelli M, Caiola E, Colombo M, Centonze G, Boeri M, et al. LKB1 Down-Modulation by miR-17 Identifies Patients With NSCLC Having Worse Prognosis Eligible for Energy-Stress–Based Treatments. J Thorac Oncol. 2021;16:1298–311.
pubmed: 33887464
doi: 10.1016/j.jtho.2021.04.005
Flory J, Lipska K. Metformin in 2019. JAMA. 2019;321:1926.
pubmed: 31009043
pmcid: 7552083
doi: 10.1001/jama.2019.3805
Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med. 2011;9:33.
pubmed: 21470407
pmcid: 3224599
doi: 10.1186/1741-7015-9-33
Pernicova I, Korbonits M. Metformin—mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143–56.
pubmed: 24393785
doi: 10.1038/nrendo.2013.256
Cha J-H, Yang W-H, Xia W, Wei Y, Chan L-C, Lim S-O, et al. Metformin Promotes Antitumor Immunity via Endoplasmic-Reticulum-Associated Degradation of PD-L1. Mol Cell. 2018;71:606-620.e7.
pubmed: 30118680
pmcid: 6786495
doi: 10.1016/j.molcel.2018.07.030
Nencioni A, Caffa I, Cortellino S, Longo VD. Fasting and cancer: molecular mechanisms and clinical application. Nat Rev Cancer. 2018;18:707–19.
pubmed: 30327499
pmcid: 6938162
doi: 10.1038/s41568-018-0061-0
Di Francesco A, Di Germanio C, Bernier M, de Cabo R. A time to fast. Science. 2018;362:770–5.
pubmed: 30442801
pmcid: 8504313
doi: 10.1126/science.aau2095
Raffaghello L, Lee C, Safdie FM, Wei M, Madia F, Bianchi G, et al. Starvation-dependent differential stress resistance protects normal but not cancer cells against high-dose chemotherapy. Proc Natl Acad Sci USA. 2008;105:8215–20.
pubmed: 18378900
pmcid: 2448817
doi: 10.1073/pnas.0708100105
Lee C, Longo VD. Fasting vs dietary restriction in cellular protection and cancer treatment: from model organisms to patients. Oncogene. 2011;30:3305–16.
pubmed: 21516129
doi: 10.1038/onc.2011.91
Manukian G, Kivolowitz C, DeAngelis T, Shastri AA, Savage JE, Camphausen K, et al. Caloric Restriction Impairs Regulatory T cells Within the Tumor Microenvironment After Radiation and Primes Effector T cells. Int J Radiat Oncol Biol Phys. 2021;110:1341–9.
pubmed: 33647370
pmcid: 8286289
doi: 10.1016/j.ijrobp.2021.02.029
Di Biase S, Lee C, Brandhorst S, Manes B, Buono R, Cheng C-W, et al. Fasting-Mimicking Diet Reduces HO-1 to Promote T Cell-Mediated Tumor Cytotoxicity. Cancer Cell. 2016;30:136–46.
pubmed: 27411588
pmcid: 5388544
doi: 10.1016/j.ccell.2016.06.005
de Groot S, Pijl H, van der Hoeven JJM, Kroep JR. Effects of short-term fasting on cancer treatment. J Exp Clin Cancer Res. 2019;38:209.
pubmed: 31113478
pmcid: 6530042
doi: 10.1186/s13046-019-1189-9
Brandhorst S, Choi IY, Wei M, Cheng CW, Sedrakyan S, Navarrete G, et al. A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan. Cell Metab. 2015;22:86–99.
pubmed: 26094889
pmcid: 4509734
doi: 10.1016/j.cmet.2015.05.012
Caiola E, Iezzi A, Tomanelli M, Bonaldi E, Scagliotti A, Colombo M, et al. LKB1 Deficiency Renders NSCLC Cells Sensitive to ERK Inhibitors. J Thorac Oncol. 2020;15:360–70.
pubmed: 31634668
doi: 10.1016/j.jtho.2019.10.009
Wang L, Cybula M, Rostworowska M, Wang L, Mucha P, Bulicz M, et al. Upregulation of Succinate Dehydrogenase (SDHA) Contributes to Enhanced Bioenergetics of Ovarian Cancer Cells and Higher Sensitivity to Anti-Metabolic Agent Shikonin. Cancers. 2022;14:5097.
pubmed: 36291881
pmcid: 9599980
doi: 10.3390/cancers14205097
Marabese M, Marchini S, Sabatino MA, Polato F, Vikhanskaya F, Marrazzo E, et al. Effects of inducible overexpression of DNp73α on cancer cell growth and response to treatment in vitro and in vivo. Cell Death Differ. 2005;12:805–14.
pubmed: 15877106
doi: 10.1038/sj.cdd.4401622
Moro M, Bertolini G, Tortoreto M, Pastorino U, Sozzi G, Roz L. Patient-Derived Xenografts of Non Small Cell Lung Cancer: Resurgence of an Old Model for Investigation of Modern Concepts of Tailored Therapy and Cancer Stem Cells. J Biomed Biotechnol. 2012;2012:1–11.
doi: 10.1155/2012/568567
Stöth M, Freire Valls A, Chen M, Hidding S, Knipper K, Shen Y, et al. Splenectomy reduces lung metastases and tumoral and metastatic niche inflammation. Int J Cancer. 2019;145:2509–20.
pubmed: 31034094
doi: 10.1002/ijc.32378
Xu H-G, Zhai Y-X, Chen J, Lu Y, Wang J-W, Quan C-S, et al. LKB1 reduces ROS-mediated cell damage via activation of p38. Oncogene. 2015;34:3848–59.
pubmed: 25263448
doi: 10.1038/onc.2014.315
Zulato E, Ciccarese F, Agnusdei V, Pinazza M, Nardo G, Iorio E, et al. LKB1 loss is associated with glutathione deficiency under oxidative stress and sensitivity of cancer cells to cytotoxic drugs and γ-irradiation. Biochem Pharmacol. 2018;156:479–90.
pubmed: 30222967
doi: 10.1016/j.bcp.2018.09.019
Kim J-W, Min DW, Kim D, Kim J, Kim MJ, Lim H, et al. GPX4 overexpressed non-small cell lung cancer cells are sensitive to RSL3-induced ferroptosis. Sci Rep. 2023;13:8872.
pubmed: 37258589
pmcid: 10232506
doi: 10.1038/s41598-023-35978-9
Iyengar P, Gandhi AY, Granados J, Guo T, Gupta A, Yu J, et al. Tumor loss-of-function mutations in STK11/LKB1 induce cachexia. JCI Insight. 2023;8:e165419.
pubmed: 37092555
pmcid: 10243820
doi: 10.1172/jci.insight.165419
Queiroz AL, Dantas E, Ramsamooj S, Murthy A, Ahmed M, Zunica ERM, et al. Blocking ActRIIB and restoring appetite reverses cachexia and improves survival in mice with lung cancer. Nat Commun. 2022;13:4633.
pubmed: 35941104
pmcid: 9360437
doi: 10.1038/s41467-022-32135-0
Yang J, Kim SH, Jung EH, Kim S, Suh KJ, Lee JY, et al. The effect of metformin or dipeptidyl peptidase 4 inhibitors on clinical outcomes in metastatic non-small cell lung cancer treated with immune checkpoint inhibitors. Thoracic Cancer. 2023;14:52–60.
pubmed: 36351567
doi: 10.1111/1759-7714.14711
Chiang C-H, Chen Y-J, Chiang C-H, Chen C-Y, Chang Y-C, Wang S-S, et al. Effect of metformin on outcomes of patients treated with immune checkpoint inhibitors: a retrospective cohort study. Cancer Immunol Immunother. 2023;72:1951–6.
pubmed: 36651967
doi: 10.1007/s00262-022-03363-6
Vernieri C, Signorelli D, Galli G, Ganzinelli M, Moro M, Fabbri A, et al. Exploiting FAsting-mimicking Diet and MEtformin to Improve the Efficacy of Platinum-pemetrexed Chemotherapy in Advanced LKB1-inactivated Lung Adenocarcinoma: The FAME Trial. Clin Lung Cancer. 2019;20:e413–7.
pubmed: 30617039
doi: 10.1016/j.cllc.2018.12.011