Targeting LKB1 in cancer-exposing and exploiting vulnerabilities

British Journal of Cancer

Volumn 113, Issue 4, 2015, Pages 574-584

  Momcilovic, M ^a   Shackelford, D B ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

cancer; LKB1; therapeutic strategies; vulnerabilities

Indexed keywords

ADENOSINE MONOPHOSPHATE ACTIVATED PROTEIN KINASE LIKE KINASE; ANTINEOPLASTIC AGENT; MAMMALIAN TARGET OF RAPAMYCIN COMPLEX 1; PHOSPHOTRANSFERASE; PHOSPHOTRANSFERASE INHIBITOR; PROTEIN KINASE LKB1; UNCLASSIFIED DRUG; PROTEIN SERINE THREONINE KINASE; TUMOR SUPPRESSOR PROTEIN;

ANTINEOPLASTIC ACTIVITY; AUTOPHAGY; CANCER PATIENT; CELL METABOLISM; CELL POLARITY; CELL SURVIVAL; CHROMOSOME 19P; DRUG TARGETING; GENE INACTIVATION; GENETIC ANALYSIS; HUMAN; LOSS OF FUNCTION MUTATION; MITOPHAGY; MOLECULARLY TARGETED THERAPY; NON SMALL CELL LUNG CANCER; NONHUMAN; PEUTZ JEGHERS SYNDROME; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; REVIEW; ANIMAL; CELL PROLIFERATION; DRUG EFFECTS; GENETICS; METABOLISM; MUTATION; NEOPLASMS; SIGNAL TRANSDUCTION;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL PROLIFERATION; HUMANS; MUTATION; NEOPLASMS; PROTEIN-SERINE-THREONINE KINASES; SIGNAL TRANSDUCTION; TUMOR SUPPRESSOR PROTEINS;

EID: 84939253550     PISSN: 00070920     EISSN: 15321827     Source Type: Journal    
DOI: 10.1038/bjc.2015.261     Document Type: Review

References (136)

1. Ahmed AA, Lu Z, Jennings NB, Etemadmoghadam D, Capalbo L, Jacamo RO, Barbosa-Morais N, Le XF. Australian Ovarian Cancer Study GVivas-Mejia P, Lopez-Berestein G, Grandjean G, Bartholomeusz G, Liao W, Andreeff M, Bowtell D, Glover DM, Sood AK, Bast Jr RC. (2010). SIK2 is a centrosome kinase required for bipolar mitotic spindle formation that provides a potential target for therapy in ovarian cancer. Cancer Cell. 18: 109-121.
2. Alachkar H, Mutonga MB, Metzeler KH, Fulton N, Malnassy G, Herold T, Spiekermann K, Bohlander SK, Hiddemann W, Matsuo Y, Stock W, Nakamura Y. (2014). Preclinical efficacy of maternal embryonic leucinezipper kinase (MELK) inhibition in acute myeloid leukemia. Oncotarget. 5: 12371-12382.
3. Algire C, Amrein L, Bazile M, David S, Zakikhani M, Pollak M. (2011). Diet and tumor LKB1 expression interact to determine sensitivity to antineoplastic effects of metformin in vivo. Oncogene. 30: 1174-1182.
4. Andrade-Vieira R, Goguen D, Bentley HA, Bowen CV, Marignani PA. (2014). Pre-clinical study of drug combinations that reduce breast cancer burden due to aberrant mTOR and metabolism promoted by LKB1 loss. Oncotarget. 5: 12738-12752.
5. Anisimov VN, Berstein LM, Egormin PA, Piskunova TS, Popovich IG, Zabezhinski MA, Kovalenko IG, Poroshina TE, Semenchenko AV, Provinciali M, Re F, Franceschi C. (2005). Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol. 40: 685-693.
6. Apsel B, Blair JA, Gonzalez B, Nazif TM, Feldman ME, Aizenstein B, Hoffman R, Williams RL, Shokat KM, Knight ZA. (2008). Targeted polypharmacology: discovery of dual inhibitors of tyrosine and phosphoinositide kinases. Nat Chem Biol. 4: 691-699.
7. Bardeesy N, Sinha M, Hezel AF, Signoretti S, Hathaway NA, Sharpless NE, Loda M, Carrasco DR, DePinho RA. (2002). Loss of the Lkb1 tumour suppressor provokes intestinal polyposis but resistance to transformation. Nature. 419: 162-167.
8. Barretina J, Caponigro G, Stransky N, Venkatesan K, Margolin AA, Kim S, Wilson CJ, Lehar J, Kryukov GV, Sonkin D, Reddy A, Liu M, Murray L, Berger MF, Monahan JE, Morais P, Meltzer J, Korejwa A, Jane-Valbuena J, Mapa FA, Thibault J, Bric-Furlong E, Raman P, Shipway A, Engels IH, Cheng J, Yu GK, Yu J, Aspesi Jr P, de Silva M, Jagtap K, Jones MD, Wang L, Hatton C, Palescandolo E, Gupta S, Mahan S, Sougnez C, Onofrio RC, Liefeld T, MacConaill L, Winckler W, Reich M, Li N, Mesirov JP, Gabriel SB, Getz G, Ardlie K, Chan V, Myer VE, Weber BL, Porter J, Warmuth M, Finan P, Harris JL, Meyerson M, Golub TR, Morrissey MP, Sellers WR, Schlegel R, Garraway LA. (2012). The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature. 483: 603-607.
9. Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G, Leonard JM, Schmithorst VJ, Laor T, Brody AS, Bean J, Salisbury S, Franz DN. (2008). Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 358: 140-151.
10. Boj SF, Hwang CI, Baker LA, Chio, Engle DD, Corbo V, Jager M, Ponz-Sarvise M, Tiriac H, Spector MS, Gracanin A, Oni T, Yu KH, van Boxtel R, Huch M, Rivera KD, Wilson JP, Feigin ME, Ohlund D, Handly-Santana A, Ardito-Abraham CM, Ludwig M, Elyada E, Alagesan B, Biffi G, Yordanov GN, Delcuze B, Creighton B, Wright K, Park Y, Morsink FH, Molenaar IQ, Borel Rinkes IH, Cuppen E, Hao Y, Jin Y, Nijman IJ, Iacobuzio-Donahue C, Leach SD, Pappin DJ, Hammell M, Klimstra DS, Basturk O, Hruban RH, Offerhaus GJ, Vries RG, Clevers H, Tuveson DA. (2015). Organoid models of human and mouse ductal pancreatic cancer. Cell. 160: 324-338.
11. Bon H, Wadhwa K, Schreiner A, Osborne M, Carroll T, Ramos-Montoya A, Ross-Adams H, Visser M, Hoffmann R, Ahmed AA, Neal DE, Mills IG. (2015). Salt-inducible kinase 2 regulates mitotic progression and transcription in prostate cancer. Mol Cancer Res. 13: 620-635.
12. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. (2006). Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 29: 254-258.
13. Carretero J, Medina PP, Pio R, Montuenga LM, Sanchez-Cespedes M. (2004). Novel and natural knockout lung cancer cell lines for the LKB1/STK11 tumor suppressor gene. Oncogene. 23: 4037-4040.
14. Carretero J, Shimamura T, Rikova K, Jackson AL, Wilkerson MD, Borgman CL, Buttarazzi MS, Sanofsky BA, McNamara KL, Brandstetter KA, Walton ZE, Gu TL, Silva JC, Crosby K, Shapiro GI, Maira SM, Ji H, Castrillon DH, Kim CF, Garcia-Echeverria C, Bardeesy N, Sharpless NE, Hayes ND, Kim WY, Engelman JA, Wong KK. (2010). Integrative genomic and proteomic analyses identify targets for Lkb1-deficient metastatic lung tumors. Cancer Cell. 17: 547-559.
15. Chen H, Huang S, Han X, Zhang J, Shan C, Tsang YH, Ma HT, Poon RY. (2014). Salt-inducible kinase 3 is a novel mitotic regulator and a target for enhancing antimitotic therapeutic-mediated cell death. Cell Death Dis. 5: e1177.
16. Chen Z, Cheng K, Walton Z, Wang Y, Ebi H, Shimamura T, Liu Y, Tupper T, Ouyang J, Li J, Gao P, Woo MS, Xu C, Yanagita M, Altabef A, Wang S, Lee C, Nakada Y, Pena CG, Sun Y, Franchetti Y, Yao C, Saur A, Cameron MD, Nishino M, Hayes DN, Wilkerson MD, Roberts PJ, Lee CB, Bardeesy N, Butaney M, Chirieac LR, Costa DB, Jackman D, Sharpless NE, Castrillon DH, Demetri GD, Janne PA, Pandolfi PP, Cantley LC, Kung AL, Engelman JA, Wong KK. (2012). A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature. 483: 613-617.
17. Cheng H, Liu P, Wang ZC, Zou L, Santiago S, Garbitt V, GjoerupOV, Iglehart JD, Miron A, Richardson AL, Hahn WC, Zhao JJ. (2009). SIK1 couples LKB1 to p53-dependent anoikis and suppresses metastasis. Sci Signal. 2: ra35.
18. Cheng H, Liu P, Zhang F, Xu E, Symonds L, Ohlson CE, Bronson RT, Maira SM, Di Tomaso E, Li J, Myers AP, Cantley LC, Mills GB, Zhao JJ. (2014). A genetic mouse model of invasive endometrial cancer driven by concurrent loss of Pten and Lkb1 Is highly responsive to mTOR inhibition. Cancer Res. 74: 15-23.
19. Contreras CM, Akbay EA, Gallardo TD, Haynie JM, Sharma S, Tagao O, Bardeesy N, Takahashi M, Settleman J, Wong KK, Castrillon DH. (2010). Lkb1 inactivation is sufficient to drive endometrial cancers that are aggressive yet highly responsive to mTOR inhibitor monotherapy. Dis Model Mech. 3: 181-193.
20. Corradetti MN, Inoki K, Bardeesy N, DePinho RA, Guan KL. (2004). Regulation of the TSC pathway by LKB1: evidence of a molecular link between tuberous sclerosis complex and Peutz-Jeghers syndrome. Genes Dev. 18: 1533-1538.
21. Crofford OB. (1995). Metformin. N Engl J Med. 333: 588-589.
22. Cui J, Yu Y, Lu GF, Liu C, Liu X, Xu YX, Zheng PY. (2013). Overexpression of ARK5 is associated with poor prognosis in hepatocellular carcinoma. Tumour Biol. 34: 1913-1918.
23. Currie CJ, Poole CD, Jenkins-Jones S, Gale EA, Johnson JA, Morgan CL. (2012). Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 35: 299-304.
24. Damsky W, Micevic G, Meeth K, Muthusamy V, Curley DP, Santhanakrishnan M, Erdelyi I, Platt JT, Huang L, Theodosakis N, Zaidi MR, Tighe S, Davies MA, Dankort D, McMahon M, Merlino G, Bardeesy N, Bosenberg M. (2015). mTORC1 activation blocks BrafV600Einduced growth arrest but is insufficient for melanoma formation. Cancer Cell. 27: 41-56.
25. de Jong M, Essers J, van Weerden WM. (2014). Imaging preclinical tumour models: improving translational power. Nat Rev Cancer. 14: 481-493.
26. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, Fulton L, Fulton RS, Zhang Q, Wendl MC, Lawrence MS, Larson DE, Chen K, Dooling DJ, Sabo A, Hawes AC, Shen H, Jhangiani SN, Lewis LR, Hall O, Zhu Y, Mathew T, Ren Y, Yao J, Scherer SE, Clerc K, Metcalf GA, Ng B, Milosavljevic A, Gonzalez-Garay ML, Osborne JR, Meyer R, Shi X, Tang Y, Koboldt DC, Lin L, Abbott R, Miner TL, Pohl C, Fewell G, Haipek C, Schmidt H, Dunford-Shore BH, Kraja A, Crosby SD, Sawyer CS, Vickery T, Sander S, Robinson J, Winckler W, Baldwin J, Chirieac LR, Dutt A, Fennell T, Hanna M, Johnson BE, Onofrio RC, Thomas RK, Tonon G, Weir BA, Zhao X, Ziaugra L, Zody MC, Giordano T, Orringer MB, Roth JA, Spitz MR, Wistuba, Ozenberger B, Good PJ, Chang AC, Beer DG, Watson MA, Ladanyi M, Broderick S, Yoshizawa A, Travis WD, Pao W, Province MA, Weinstock GM, Varmus HE, Gabriel SB, Lander ES, Gibbs RA, Meyerson M, Wilson RK. (2008). Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 455: 1069-1075.
27. Dowling RJ, Niraula S, Stambolic V, Goodwin PJ. (2012). Metformin in cancer: translational challenges. J Mol Endocrinol. 48: R31-R43.
28. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM, Capdeville R, Talpaz M. (2001). Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 344: 1038-1042.
29. Du T, Qu Y, Li J, Li H, Su L, Zhou Q, Yan M, Li C, Zhu Z, Liu B. (2014). Maternal embryonic leucine zipper kinase enhances gastric cancer progression via the FAK/Paxillin pathway. Mol Cancer. 13: 100.
30. Dykens JA, Jamieson J, Marroquin L, Nadanaciva S, Billis PA, Will Y. (2008). Biguanide-induced mitochondrial dysfunction yields increased lactate production and cytotoxicity of aerobically-poised HepG2 cells and human hepatocytes in vitro. Toxicol Appl Pharmacol. 233: 203-210.
31. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ. (2011). Phosphorylation of ULK1 (hATG1) by AMP-Activated protein kinase connects energy sensing to mitophagy. Science. 331: 456-461.
32. Emmanuel C, Gava N, Kennedy C, Balleine RL, Sharma R, Wain G, Brand A, Hogg R, Etemadmoghadam D, George J. Australian Ovarian Cancer Study GBirrer MJ, Clarke CL, Chenevix-Trench G, Bowtell DD, Harnett PR, deFazio A. (2011). Comparison of expression profiles in ovarian epithelium in vivo and ovarian cancer identifies novel candidate genes involved in disease pathogenesis. PLoS One. 6: e17617.
33. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, Garcia-Echeverria C, Weissleder R, Mahmood U, Cantley LC, Wong KK. (2008). Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 14: 1351-1356.
34. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. (2005). Metformin and reduced risk of cancer in diabetic patients. BMJ. 330: 1304-1305.
35. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM. (2009). Active-site inhibitors of mTOR target rapamycinresistant outputs of mTORC1 and mTORC2. PLoS Biol. 7: e38.
36. Fernandez P, Carretero J, Medina PP, Jimenez AI, Rodriguez-Perales S, Paz MF, Cigudosa JC, Esteller M, Lombardia L, Morente M, Sanchez-Verde L, Sotelo T, Sanchez-Cespedes M. (2004). Distinctive gene expression of human lung adenocarcinomas carrying LKB1 mutations. Oncogene. 23: 5084-5091.
37. Fillmore CM, Xu C, Desai PT, Berry JM, Rowbotham SP, Lin YJ, Zhang H, Marquez VE, Hammerman PS, Wong KK, Kim CF. (2015). EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors. Nature. 520: 239-242.
38. Fimognari FL, Pastorelli R, Incalzi RA. (2006). Phenformin-induced lactic acidosis in an older diabetic patient: a recurrent drama (phenformin and lactic acidosis). Diabetes Care. 29: 950-951.
39. Fu X, Guadagni F, Hoffman RM. (1992). A metastatic nude-mouse model of human pancreatic cancer constructed orthotopically with histologically intact patient specimens. Proc Natl Acad Sci USA. 89: 5645-5649.
40. Fu XY, Besterman JM, Monosov A, Hoffman RM. (1991). Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically intact patient specimens. Proc Natl Acad Sci USA. 88: 9345-9349.
41. Gan B, Hu J, Jiang S, Liu Y, Sahin E, Zhuang L, Fletcher-Sananikone E, Colla S, Wang YA, Chin L, Depinho RA. (2010). Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells. Nature. 468: 701-704.
42. Gandara DR, Mack PC, Bult C, Li T, Lara Jr PN, Riess JW, Astrow SH, Gandour-Edwards R, Cooke DT, Yoneda KY, Moore EH, Pan CX, Burich RA, David EA, Keck JG, Airhart S, Goodwin N, de Vere White RW, Liu ET. (2015). Bridging tumor genomics to patient outcomes through an integrated patient-derived xenograft platform. Clin Lung Cancer. 16: 165-172.
43. Gandhi L, McNamara KL, Li D, Borgman CL, McDermott U, Brandstetter KA, Padera RF, Chirieac LR, Settleman JE, Wong KK. (2009). Sunitinib prolongs survival in genetically engineered mouse models of multistep lung carcinogenesis. Cancer Prev Res (Phila) 2: 330-337.
44. Gao Y, Xiao Q, Ma H, Li L, Liu J, Feng Y, Fang Z, Wu J, Han X, Zhang J, Sun Y, Wu G, Padera R, Chen H, Wong KK, Ge G, Ji H. (2010). LKB1 inhibits lung cancer progression through lysyl oxidase and extracellular matrix remodeling. Proc Natl Acad Sci USA. 107: 18892-18897.
45. Goodwin JM, Svensson RU, Lou HJ, Winslow MM, Turk BE, Shaw RJ. (2014). An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential. Mol Cell. 55: 436-450.
46. Gorboulev V, Ulzheimer JC, Akhoundova A, Ulzheimer-Teuber I, Karbach U, Quester S, Baumann C, Lang F, Busch AE, Koepsell H. (1997). Cloning and characterization of two human polyspecific organic cation transporters. DNA Cell Biol. 16: 871-881.
47. Guo JY, Chen HY, Mathew R, Fan J, Strohecker AM, Karsli-Uzunbas G, Kamphorst JJ, Chen G, Lemons JM, Karantza V, Coller HA, Dipaola RS, Gelinas C, Rabinowitz JD, White E. (2011). Activated Ras requires autophagy to maintain oxidative metabolism and tumorigenesis. Genes Dev. 25: 460-470.
48. Gurumurthy S, Xie SZ, Alagesan B, Kim J, Yusuf RZ, Saez B, Tzatsos A, Ozsolak F, Milos P, Ferrari F, Park PJ, Shirihai OS, Scadden DT, Bardeesy N. (2010). The Lkb1 metabolic sensor maintains haematopoietic stem cell survival. Nature. 468: 659-663.
49. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ. (2008). AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell. 30: 214-226.
50. Hardie DG, Carling D, Gamblin SJ. (2011). AMP-Activated protein kinase: also regulated by ADP?. Trends Biochem Sci. 36: 470-477.
51. Hardie DG, Ross FA, Hawley SA. (2012). AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 13: 251-262.
52. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Makela TP, Alessi DR, Hardie DG. (2003). Complexes between the LKB1 tumor suppressor, STRADalpha/beta and MO25alpha/beta are upstream kinases in the AMP-Activated protein kinase cascade. J Biol. 2: 28.
53. Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, Frenguelli BG, Hardie DG. (2005). Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-Activated protein kinase. Cell Metab. 2: 9-19.
54. Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM, Hardie DG. (2010). Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 11: 554-565.
55. Hayer-Zillgen M, Bruss M, Bonisch H. (2002). Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3. Br J Pharmacol. 136: 829-836.
56. Hemminki A. (1999). The molecular basis and clinical aspects of Peutz-Jeghers syndrome. Cell Mol Life Sci. 55: 735-750.
57. Hemminki A, Markie D, Tomlinson I, Avizienyte E, Roth S, Loukola A, Bignell G, Warren W, Aminoff M, Hoglund P, Jarvinen H, Kristo P, Pelin K, Ridanpaa M, Salovaara R, Toro T, Bodmer W, Olschwang S, Olsen AS, Stratton MR, de la Chapelle A, Aaltonen LA. (1998). A serine/.threonine kinase gene defective in Peutz-Jeghers syndrome. Nature. 391: 184-187.
58. Hoffman GR, Rahal R, Buxton F, Xiang K, McAllister G, Frias E, Bagdasarian L, Huber J, Lindeman A, Chen D, Romero R, Ramadan N, Phadke T, Haas K, Jaskelioff M, Wilson BG, Meyer MJ, Saenz-Vash V, Zhai H, Myer VE, Porter JA, Keen N, McLaughlin ME, Mickanin C, Roberts CW, Stegmeier F, Jagani Z. (2014). Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers. Proc Natl Acad Sci USA. 111: 3128-3133.
59. Hong SP, Leiper FC, Woods A, Carling D, Carlson M. (2003). Activation of yeast Snf1 and mammalian AMP-Activated protein kinase by upstream kinases. Proc Natl Acad Sci USA. 100: 8839-8843.
60. Hurley RL, Anderson KA, Franzone JM, Kemp BE, Means AR, Witters LA. (2005). The Ca2+/calmodulin-dependent protein kinase kinases are AMP-Activated protein kinase kinases. J Biol Chem. 280: 29060-29066.
61. Inge LJ, Friel JM, Richer AL, Fowler AJ, Whitsett T, Smith MA, Tran NL, Bremner RM. (2014). LKB1 inactivation sensitizes non-small cell lung cancer to pharmacological aggravation of ER stress. Cancer Lett. 352: 187-195.
62. Inoki K, Zhu T, Guan KL. (2003). TSC2 mediates cellular energy response to control cell growth and survival. Cell. 115: 577-590.
63. Janus N, Thariat J, Boulanger H, Deray G, Launay-Vacher V. (2010). Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol. 21: 1395-1403.
64. Ji H, Ramsey MR, Hayes DN, Fan C, McNamara K, Kozlowski P, Torrice C, Wu MC, Shimamura T, Perera SA, Liang MC, Cai D, Naumov GN, Bao L, Contreras CM, Li D, Chen L, Krishnamurthy J, Koivunen J, Chirieac LR, Padera RF, Bronson RT, Lindeman NI, Christiani DC, Lin X, Shapiro GI, Janne PA, Johnson BE, Meyerson M, Kwiatkowski DJ, Castrillon DH, Bardeesy N, Sharpless NE, Wong KK. (2007). LKB1 modulates lung cancer differentiation and metastasis. Nature. 448: 807-810.
65. Jishage K, Nezu J, Kawase Y, Iwata T, Watanabe M, Miyoshi A, Ose A, Habu K, Kake T, Kamada N, Ueda O, Kinoshita M, Jenne DE, Shimane M, Suzuki H. (2002). Role of Lkb1, the causative gene of Peutz-Jegher's syndrome, in embryogenesis and polyposis. Proc Natl Acad Sci USA. 99: 8903-8908.
66. Katajisto P, Vaahtomeri K, Ekman N, Ventela E, Ristimaki A, Bardeesy N, Feil R, DePinho RA, Makela TP. (2008). LKB1 signaling in mesenchymal cells required for suppression of gastrointestinal polyposis. Nat Genet. 40: 455-459.
67. Kaufman JM, Amann JM, Park K, Arasada RR, Li H, Shyr Y, Carbone DP. (2014). LKB1 Loss induces characteristic patterns of gene expression in human tumors associated with NRF2 activation and attenuation of PI3K-AKT. J Thorac Oncol. 9: 794-804.
68. Kim HS, Mendiratta S, Kim J, Pecot CV, Larsen JE, Zubovych I, Seo BY, Kim J, Eskiocak B, Chung H, McMillan E, Wu S, De Brabander J, Komurov K, Toombs JE, Wei S, Peyton M, Williams N, Gazdar AF, Posner BA, Brekken RA, Sood AK, Deberardinis RJ, Roth MG, Minna JD, White MA. (2013). Systematic identification of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell. 155: 552-566.
69. Kline ER, Muller S, Pan L, Tighiouart M, Chen ZG, Marcus AI. (2011). Localization-specific LKB1 loss in head and neck squamous cell carcinoma metastasis. Head Neck. 33: 1501-1512.
70. Kline ER, Shupe J, Gilbert-Ross M, Zhou W, Marcus AI. (2013). LKB1 represses focal adhesion kinase (FAK) signaling via a FAK-LKB1 complex to regulate FAK site maturation and directional persistence. J Biol Chem. 288: 17663-17674.
71. Kuner R, Falth M, Pressinotti NC, Brase JC, Puig SB, Metzger J, Gade S, Schafer G, Bartsch G, Steiner E, Klocker H, Sultmann H. (2013). The maternal embryonic leucine zipper kinase (MELK) is upregulated in highgrade prostate cancer. J Mol Med (Berl) 91: 237-248.
72. Kusakai G, Suzuki A, Ogura T, Miyamoto S, Ochiai A, Kaminishi M, Esumi H. (2004). ARK5 expression in colorectal cancer and its implications for tumor progression. Am J Pathol. 164: 987-995.
73. Lalau JD. (2010). Lactic acidosis induced by metformin: incidence, management and prevention. Drug safety. 33: 727-740.
74. Li X, Nadauld L, Ootani A, Corney DC, Pai RK, Gevaert O, Cantrell MA, Rack PG, Neal JT, Chan CW, Yeung T, Gong X, Yuan J, Wilhelmy J, Robine S, Attardi LD, Plevritis SK, Hung KE, Chen CZ, Ji HP, Kuo CJ. (2014). Oncogenic transformation of diverse gastrointestinal tissues in primary organoid culture. Nat Med. 20: 769-777.
75. Liang MC, Ma J, Chen L, Kozlowski P, Qin W, Li D, Goto J, Shimamura T, Hayes DN, Meyerson M, Kwiatkowski DJ, Wong KK. (2010). TSC1 loss synergizes with KRAS activation in lung cancer development in the mouse and confers rapamycin sensitivity. Oncogene. 29: 1588-1597.
76. Liu L, Ulbrich J, Muller J, Wustefeld T, Aeberhard L, Kress TR, Muthalagu N, Rycak L, Rudalska R, Moll R, Kempa S, Zender L, Eilers M, Murphy DJ. (2012). Deregulated MYC expression induces dependence upon AMPKrelated kinase 5. Nature. 483: 608-612.
77. Liu W, Monahan KB, Pfefferle AD, Shimamura T, Sorrentino J, Chan KT, Roadcap DW, Ollila DW, Thomas NE, Castrillon DH, Miller CR, Perou CM, Wong KK, Bear JE, Sharpless NE. (2012). LKB1/STK11 inactivation leads to expansion of a prometastatic tumor subpopulation in melanoma. Cancer Cell. 21: 751-764.
78. Liu Y, Marks K, Cowley GS, Carretero J, Liu Q, Nieland TJ, Xu C, Cohoon TJ, Gao P, Zhang Y, Chen Z, Altabef AB, Tchaicha JH, Wang X, Choe S, Driggers EM, Zhang J, Bailey ST, Sharpless NE, Hayes DN, Patel NM, Janne PA, Bardeesy N, Engelman JA, Manning BD, Shaw RJ, Asara JM, Scully R, Kimmelman A, Byers LA, Gibbons DL, Wistuba, Heymach JV, Kwiatkowski DJ, Kim WY, Kung AL, Gray NS, Root DE, Cantley LC, Wong KK. (2013). Metabolic and functional genomic studies identify deoxythymidylate kinase as a target in LKB1-mutant lung cancer. Cancer Discov. 3: 870-879.
79. Lu S, Niu N, Guo H, Tang J, Guo W, Liu Z, Shi L, Sun T, Zhou F, Li H, Zhang J, Zhang B. (2013). ARK5 promotes glioma cell invasion, and its elevated expression is correlated with poor clinical outcome. Eur J Cancer. 49: 752-763.
80. Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Garcia-Echeverria C. (2008). Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 7: 1851-1863.
81. Martin-Belmonte F, Perez-Moreno M. (2012). Epithelial cell polarity, stem cells and cancer. Nat Rev Cancer. 12: 23-38.
82. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, Brown KK, Lynch 3rd JP, Goldberg HJ, Young LR, Kinder BW, Downey GP, Sullivan EJ, Colby TV, McKay RT, Cohen MM, Korbee L, Taveira-DaSilva AM, Lee HS, Krischer JP, Trapnell BC. (2011). Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med. 364: 1595-1606.
83. Medina PP, Romero OA, Kohno T, Montuenga LM, Pio R, Yokota J, Sanchez-Cespedes M. (2008). Frequent BRG1/SMARCA4-inactivating mutations in human lung cancer cell lines. Hum Mutat. 29: 617-622.
84. Mihaylova MM, Shaw RJ. (2011). The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 13: 1016-1023.
85. Miyoshi H, Nakau M, Ishikawa TO, Seldin MF, Oshima M, Taketo MM. (2002). Gastrointestinal hamartomatous polyposis in Lkb1 heterozygous knockout mice. Cancer Res. 62: 2261-2266.
86. Mohseni M, Sun J, Lau A, Curtis S, Goldsmith J, Fox VL, Wei C, Frazier M, Samson O, Wong KK, Kim C, Camargo FD. (2014). A genetic screen identifies an LKB1-MARK signalling axis controlling the Hippo-YAP pathway. Nat Cell Biol. 16: 108-117.
87. Nakada D, Saunders TL, Morrison SJ. (2010). Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells. Nature. 468: 653-658.
88. Nakada Y, Stewart TG, Pena CG, Zhang S, Zhao N, Bardeesy N, Sharpless NE, Wong KK, Hayes DN, Castrillon DH. (2013). The LKB1 tumor suppressor as a biomarker in mouse and human tissues. PloS One. 8: e73449.
89. Namiki T, Tanemura A, Valencia JC, Coelho SG, Passeron T, Kawaguchi M, Vieira WD, Ishikawa M, Nishijima W, Izumo T, Kaneko Y, Katayama I, Yamaguchi Y, Yin L, Polley EC, Liu H, Kawakami Y, Eishi Y, Takahashi E, Yokozeki H, Hearing VJ. (2011). AMP kinase-related kinase NUAK2 affects tumor growth, migration, and clinical outcome of human melanoma. Proc Natl Acad Sci USA. 108: 6597-6602.
90. Nardella C, Lunardi A, Patnaik A, Cantley LC, Pandolfi PP. (2011). The APL paradigm and the 'co-clinical trial' project. Cancer Discov. 1: 108-116.
91. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66: 1500-1508.
92. Oakhill JS, Steel R, Chen ZP, Scott JW, Ling N, Tam S, Kemp BE. (2011). AMPK is a direct adenylate charge-regulated protein kinase. Science. 332: 1433-1435.
93. Ohara G, Miyazaki K, Kurishima K, Kagohashi K, Ishikawa H, Satoh H, Hizawa N. (2012). Safety creatinine clearance level for platinum chemotherapy in lung cancer patients. Oncol Lett. 3: 311-314.
94. Ollila S, Makela TP. (2011). The tumor suppressor kinase LKB1: lessons from mouse models. J Mol Cell Biol. 3: 330-340.
95. Osoegawa A, Kometani T, Nosaki K, Ondo K, Hamatake M, Hirai F, Seto T, Sugio K, Ichinose Y. (2011). LKB1 mutations frequently detected in mucinous bronchioloalveolar carcinoma. Jpn J Clin Oncol. 41: 1132-1137.
96. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. (2013). K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 503: 548-551.
97. Owen MR, Doran E, Halestrap AP. (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 348: 607-614.
98. Pickard MR, Green AR, Ellis IO, Caldas C, Hedge VL, Mourtada-Maarabouni M, Williams GT. (2009). Dysregulated expression of Fau and MELK is associated with poor prognosis in breast cancer. Breast Cancer Res. 11: R60.
99. Pineda CT, Ramanathan S, Fon Tacer K, Weon JL, Potts MB, Ou YH, White MA, Potts PR. (2015). Degradation of AMPK by a cancer-specific ubiquitin ligase. Cell. 160: 715-728.
100. Pollak M. (2010). Metformin and other biguanides in oncology: advancing the research agenda. Cancer Prev Res (Phila) 3: 1060-1065.
101. Qi WX, Tang LN, He AN, Yao Y, Shen Z. (2013). Incidence and risk of treatment-related mortality in cancer patients treated with EGFR-TKIs: a meta-Analysis of 22 phase III randomized controlled trials. Respir Med. 107: 1280-1283.
102. Rines AK, Burke MA, Fernandez RP, Volpert OV, Ardehali H. (2012). Snf1-related kinase inhibits colon cancer cell proliferation through calcyclin-binding protein-dependent reduction of beta-catenin. FASEB J. 26: 4685-4695.
103. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, Poulikakos PI, Scaltriti M, Moskatel E, Baselga J, Guichard S, Rosen N. (2011). mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1: 248-259.
104. Roh SA, Choi EY, Cho DH, Jang SJ, Kim SY, Kim YS, Kim JC. (2010). Growth and invasion of sporadic colorectal adenocarcinomas in terms of genetic change. J Korean Med Sci. 25: 353-360.
105. Rossi DJ, Ylikorkala A, Korsisaari N, Salovaara R, Luukko K, Launonen V, Henkemeyer M, Ristimaki A, Aaltonen LA, Makela TP. (2002). Induction of cyclooxygenase-2 in a mouse model of Peutz-Jeghers polyposis. Proc Natl Acad Sci USA. 99: 12327-12332.
106. Sanchez-Cespedes M. (2007). A role for LKB1 gene in human cancer beyond the Peutz-Jeghers syndrome. Oncogene. 26: 7825-7832.
107. Sanchez-Cespedes M, Parrella P, Esteller M, Nomoto S, Trink B, Engles JM, Westra WH, Herman JG, Sidransky D. (2002). Inactivation of LKB1/STK11 is a common event in adenocarcinomas of the lung. Cancer Res. 62: 3659-3662.
108. Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Standop J, Ding XZ, Adrian TE, Pour PM. (2001). Prevention of pancreatic cancer induction in hamsters by metformin. Gastroenterology. 120: 1263-1270.
109. Segal ED, Yasmeen A, Beauchamp MC, Rosenblatt J, Pollak M, Gotlieb WH. (2011). Relevance of the OCT1 transporter to the antineoplastic effect of biguanides. Biochem Biophys Res Commun. 414: 694-699.
110. Selvik LK, Rao S, Steigedal TS, Haltbakk I, Misund K, Bruland T, Prestvik WS, Laegreid A, Thommesen L. (2014). Salt-inducible kinase 1 (SIK1) is induced by gastrin and inhibits migration of gastric adenocarcinoma cells. PLoS One. 9: e112485.
111. Shackelford DB. (2013). Unravelling the connection between metabolism and tumorigenesis through studies of the liver kinase B1 tumour suppressor. J Carcinog. 12: 16.
112. Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, Wei L, Fishbein MC, Czernin J, Mischel PS, Shaw RJ. (2013). LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 23: 143-158.
113. Shackelford DB, Abt E, Gerken L, Vasquez DS, Seki A, Leblanc M, Wei L, Fishbein MC, Czernin J, Mischel PS, Shaw RJ. (2013). LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin. Cancer Cell. 23(2): 143-158.
114. Shackelford DB, Shaw RJ. (2009). The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 9: 563-575.
115. Shackelford DB, Vasquez DS, Corbeil J, Wu S, Leblanc M, Wu CL, Vera DR, Shaw RJ. (2009). mTOR and HIF-1alpha-mediated tumor metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc Natl Acad Sci USA. 106: 11137-11142.
116. Shackelford DB, Vasquez DS, Corbiel J, Wu S, Leblanc M, Wu CL, Vera DR, Shaw RJ. (2009). mTOR-dependent regulation of polyposis and HIF-1a mediated glucose metabolism in an LKB1 mouse model of Peutz-Jeghers syndrome. Proc Natl Acad Sci USA. in press. 106: 11137-11142.
117. Shaw RJ, Bardeesy N, Manning BD, Lopez L, Kosmatka M, DePinho RA, Cantley LC. (2004). The LKB1 tumor suppressor negatively regulates mTOR signaling. Cancer Cell. 6: 91-99.
118. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC. (2004). The tumor suppressor LKB1 kinase directly activates AMP-Activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA. 101: 3329-3335.
119. Shorning BY, Griffiths D, Clarke AR. (2011). Lkb1 and Pten synergise to suppress mTOR-mediated tumorigenesis and epithelial-mesenchymal transition in the mouse bladder. PloS One. 6: e16209.
120. Strohecker AM, Guo JY, Karsli-Uzunbas G, Price SM, Chen GJ, Mathew R, McMahon M, White E. (2013). Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors. Cancer Discov. 3: 1272-1285.
121. Suzuki A, Iida S, Kato-Uranishi M, Tajima E, Zhan F, Hanamura I, Huang Y, Ogura T, Takahashi S, Ueda R, Barlogie B, Shaughnessy Jr J, Esumi H. (2005). ARK5 is transcriptionally regulated by the large-MAF family and mediates IGF-1-induced cell invasion in multiple myeloma: ARK5 as a new molecular determinant of malignant multiple myeloma. Oncogene. 24: 6936-6944.
122. Suzuki A, Lu J, Kusakai G, Kishimoto A, Ogura T, Esumi H. (2004). ARK5 is a tumor invasion-Associated factor downstream of Akt signaling. Mol Cell Biol. 24: 3526-3535.
123. Tanwar PS, Kaneko-Tarui T, Zhang L, Tanaka Y, Crum CP, Teixeira JM. (2012). Stromal liver kinase B1 [STK11] signaling loss induces oviductal adenomas and endometrial cancer by activating mammalian target of rapamycin complex 1. PLoS Genet. 8: e1002906.
124. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. (2012). Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 366: 2443-2454.
125. Wander SA, Hennessy BT, Slingerland JM. (2011). Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy. J Clin Invest. 121: 1231-1241.
126. Wang H, Liu XB, Chen JH, Wang QQ, Chen JP, Xu JF, Sheng CY, Ni QC. (2014). Decreased expression and prognostic role of cytoplasmic BRSK1 in human breast carcinoma: correlation with Jab1 stability and PI3K/Akt pathway. Exp Mol Pathol. 97: 191-201.
127. Wei C, Amos CI, Zhang N, Wang X, Rashid A, Walker CL, Behringer RR, Frazier ML. (2008). Suppression of Peutz-Jeghers polyposis by targeting mammalian target of rapamycin signaling. Clin Cancer Res. 14: 1167-1171.
128. Wilkerson MD, Yin X, Walter V, Zhao N, Cabanski CR, Hayward MC, Miller CR, Socinski MA, Parsons AM, Thorne LB, Haithcock BE, Veeramachaneni NK, Funkhouser WK, Randell SH, Bernard PS, Perou CM, Hayes DN. (2012). Differential pathogenesis of lung adenocarcinoma subtypes involving sequence mutations, copy number, chromosomal instability, and methylation. PloS One. 7: e36530.
129. Wingo SN, Gallardo TD, Akbay EA, Liang MC, Contreras CM, Boren T, Shimamura T, Miller DS, Sharpless NE, Bardeesy N, Kwiatkowski DJ, Schorge JO, Wong KK, Castrillon DH. (2009). Somatic LKB1 mutations promote cervical cancer progression. PLoS One. 4: e5137.
130. Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, Carlson M, Carling D. (2005). C(Ca2+)/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-Activated protein kinase in mammalian cells. Cell Metab. 2: 21-33.
131. Woods A, Johnstone SR, Dickerson K, Leiper FC, Fryer LG, Neumann D, Schlattner U, Wallimann T, Carlson M, Carling D. (2003). LKB1 is the upstream kinase in the AMP-Activated protein kinase cascade. Curr Biol. 13: 2004-2008.
132. Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF, Saiu P, Howell SA, Aasland R, Martin SR, Carling D, Gamblin SJ. (2011). Structure of mammalian AMPK and its regulation by ADP. Nature. 472: 230-233.
133. Xu C, Fillmore CM, Koyama S, Wu H, Zhao Y, Chen Z, Herter-Sprie GS, Akbay EA, Tchaicha JH, Altabef A, Reibel JB, Walton Z, Ji H, Watanabe H, Janne PA, Castrillon DH, Rustgi AK, Bass AJ, Freeman GJ, Padera RF, Dranoff G, Hammerman PS, Kim CF, Wong KK. (2014). Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell. 25: 590-604.
134. Ylikorkala A, Rossi DJ, Korsisaari N, Luukko K, Alitalo K, Henkemeyer M, Makela TP. (2001). Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice. Science. 293: 1323-1326.
135. Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S, Soh BS, Sun LL, Tai BC, Nga ME, Bhakoo KK, Jayapal SR, Nichane M, Yu Q, Ahmed DA, Tan C, Sing WP, Tam J, Thirugananam A, Noghabi MS, Pang YH, Ang HS, Mitchell W, Robson P, Kaldis P, Soo RA, Swarup S, Lim EH, Lim B. (2012). Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell. 148: 259-272.
136. Zheng B, Jeong JH, Asara JM, Yuan YY, Granter SR, Chin L, Cantley LC. (2009). Oncogenic B-RAF negatively regulates the tumor suppressor LKB1 to promote melanoma cell proliferation. Mol Cell. 33: 237-247.