The PI3K/AKT pathway as a target for cancer treatment

Annual Review of Medicine

Volumn 67, Issue , 2016, Pages 11-28

  Mayer, Ingrid A ^a   Arteaga, Carlos L ^a  

^a VANDERBILT INGRAM CANCER CENTER   (United States)

Author keywords

Breast cancer; Lymphoproliferative disorders; Mammalian target of rapamycin (mTOR); Mutation; Pathway inhibitors; Phosphoinositide 3 kinase (PI3K) AKT

Indexed keywords

2 (2 DIFLUOROMETHYLBENZIMIDAZOL 1 YL) 4,6 DIMORPHOLINO 1,3,5 TRIAZINE; 8 (6 METHOXY 3 PYRIDINYL) 3 METHYL 1 [4 (1 PIPERAZINYL) 3 (TRIFLUOROMETHYL)PHENYL] 1H IMIDAZO[4,5 C]QUINOLIN 2(3H) ONE; ALPELISIB; APITOLISIB; BUPARLISIB; CH 5132799; COPANLISIB; DACTOLISIB; DS 7423; DUVELISIB; GEDATOLISIB; IDELALISIB; INK 1117; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MLN 1117; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PICTILISIB; PILARALISIB; PROTEIN KINASE B; PWT 33597; SONOLISIB; TASELISIB; UNCLASSIFIED DRUG; VOXTALISIB; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR 2; ERBB2 PROTEIN, HUMAN; ESTROGEN RECEPTOR; MTOR PROTEIN, HUMAN; PROTEIN KINASE INHIBITOR; PROTEIN TYROSINE KINASE; TARGET OF RAPAMYCIN KINASE;

ADVANCED CANCER; ARTICLE; ASTROCYTOMA; BREAST CANCER; CANCER THERAPY; CHRONIC LYMPHATIC LEUKEMIA; COLORECTAL CANCER; DRUG TARGETING; ENDOMETRIUM CANCER; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; FEEDBACK SYSTEM; GASTROINTESTINAL STROMAL TUMOR; GENE MUTATION; GLIOBLASTOMA; HEMATOLOGIC MALIGNANCY; HER2 POSITIVE BREAST CANCER; HUMAN; KIDNEY CARCINOMA; LEUKEMIA; LYMPHOMA; LYMPHOPROLIFERATIVE DISEASE; MELANOMA; MULTIPLE MYELOMA; NON SMALL CELL LUNG CANCER; NONHODGKIN LYMPHOMA; ONCOGENE; OVARY CANCER; PANCREATIC NEUROENDOCRINE TUMOR; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROSTATE CANCER; SOLID TUMOR; ANTAGONISTS AND INHIBITORS; BREAST NEOPLASMS; CHEMISTRY; DRUG EFFECTS; FEMALE; GENETICS; LYMPHOPROLIFERATIVE DISORDERS; METABOLISM; MOLECULARLY TARGETED THERAPY; PROCEDURES; SIGNAL TRANSDUCTION;

ANTINEOPLASTIC AGENTS; BREAST NEOPLASMS; FEMALE; HUMANS; LYMPHOPROLIFERATIVE DISORDERS; MOLECULAR TARGETED THERAPY; PHOSPHATIDYLINOSITOL 3-KINASE; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; RECEPTOR PROTEIN-TYROSINE KINASES; RECEPTOR, ERBB-2; RECEPTORS, ESTROGEN; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES;

EID: 84954523816     PISSN: 00664219     EISSN: 1545326X     Source Type: Book Series    
DOI: 10.1146/annurev-med-062913-051343     Document Type: Article

References (90)

1. Engelman JA. (2009). Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer 9: 550-62
2. Engelman JA, Luo J, Cantley LC. (2006). The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7: 606-19
3. Salmena L, Carracedo A, Pandolfi PP. (2008). Tenets of PTEN tumor suppression. Cell 133: 403-14
4. Manning BD, Cantley LC. (2007). AKT/PKB signaling: navigating downstream. Cell 129: 1261-74
5. Guertin DA, Sabatini DM. (2007). Defining the role of mTOR in cancer. Cancer Cell 12: 9-22
6. Thorpe LM, Yuzugullu H, Zhao JJ. (2015). PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat. Rev. Cancer 15: 7-24
7. Ciraolo E, Morello F, Hobbs RM, et al. (2010). Essential role of the p110beta subunit of phosphoinositide 3-OH kinase in male fertility. Mol. Biol. Cell 21: 704-11
8. Okkenhaug K, Bilancio A, Farjot G, et al. (2002). Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297: 1031-34
9. Sasaki T, Suzuki A, Sasaki J, Penninger JM. (2002). Phosphoinositide 3-kinases in immunity: lessons from knockout mice. J. Biochem. 131: 495-501
10. Huang CH, Mandelker D, Schmidt-Kittler O, et al. (2007). The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318: 1744-48
11. Hao Y, Wang C, Cao B, et al. (2013). Gain of interaction with IRS1 by p110alpha-helical domain mutants is crucial for their oncogenic functions. Cancer Cell 23: 583-93
12. Burke JE, Perisic O, Masson GR, et al. (2012). Oncogenic mutations mimic and enhance dynamic events in the natural activation of phosphoinositide 3-kinase p110alpha (PIK3CA). PNAS 109: 15259-64
13. Engelman JA, Chen L, Tan X, et al. (2008). Effective use of PI3K andMEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat. Med. 14: 1351-56
14. Liu P, Cheng H, Santiago S, et al. (2011). Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway-dependent and PI3K pathway-independent mechanisms. Nat. Med. 17: 1116-20
15. Kinross KM, Montgomery KG, Kleinschmidt M, et al. (2012). An activating Pik3ca mutation coupled with Pten loss is sufficient to initiate ovarian tumorigenesis in mice. J. Clin. Investig. 122: 553-57
16. Philp AJ, Campbell IG, Leet C, et al. (2001). The phosphatidylinositol 3-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res. 61: 7426-29
17. Jaiswal BS, Janakiraman V, Kljavin NM, et al. (2009). Somaticmutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 16: 463-74
18. Taniguchi CM, Winnay J, Kondo T, et al. (2010). The phosphoinositide 3-kinase regulatory subunit p85alpha can exert tumor suppressor properties through negative regulation of growth factor signaling. Cancer Res. 70: 5305-15
19. Luo J, Sobkiw CL, Logsdon NM, et al. (2005). Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/-mice by the p85 regulatory subunits of phosphoinositide 3-kinase. PNAS 102: 10238-43
20. Cortes I, Sanchez-Ruiz J, Zuluaga S, et al. (2012). p85beta phosphoinositide 3-kinase subunit regulates tumor progression. PNAS 109: 11318-23
21. Utermark T, Rao T, Cheng H, et al. (2012). The p110alpha and p110beta isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis. Genes Dev. 26: 1573-86
22. Castellano E, Sheridan C, Thin MZ, et al. (2013). Requirement for interaction of PI3-kinase p110alpha with RAS in lung tumor maintenance. Cancer Cell 24: 617-30
23. Gritsman K, Yuzugullu H, Von T, et al. (2014). Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110alpha. J. Clin. Invest. 124: 1794-809
24. Dbouk HA, Vadas O, Shymanets A, et al. 2012.Gprotein-coupled receptor-mediated activation of p110β by Gβ?is required for cellular transformation and invasiveness. Sci. Signal. 5: ra89
25. Jia S, Liu Z, Zhang S, et al. (2008). Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454: 776-79
26. Wang Q, Von T, Bronson R, et al. (2013). Spatially distinct roles of class Ia PI3K isoforms in the development and maintenance of PTEN hamartoma tumor syndrome. Genes Dev. 27: 1568-80
27. Weigelt B, Warne PH, Lambros MB, et al. (2013). PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin. Cancer Res. 19: 3533-44
28. Costa C, Ebi H, Martini M, et al. (2015). Measurement of PIP3 levels reveals an unexpected role for p110beta in early adaptive responses to p110alpha-specific inhibitors in luminal breast cancer. Cancer Cell 27: 97-108
29. Juric D, Castel P, Griffith M, et al. (2015). Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor. Nature 518: 240-44
30. Cancer Genome Atlas Network Collaborators. (2012). Comprehensivemolecular portraits of human breast tumours. Nature 490: 61-70
31. Cancer Genome Atlas Research Network Collaborators. (2008). Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455: 1061-68
32. Iyer G, Hanrahan AJ, Milowsky MI, et al. (2012). Genome sequencing identifies a basis for everolimus sensitivity. Science 338: 221
33. Wagle N, Grabiner BC, Van Allen EM, et al. (2014). Response and acquired resistance to everolimus in anaplastic thyroid cancer. N. Engl. J. Med. 371: 1426-33
34. Wagle N, Grabiner BC, Van Allen EM, et al. (2014). Activating mTOR mutations in a patient with an extraordinary response on a phase I trial of everolimus and pazopanib. Cancer Discov. 4: 546-53
35. Chandarlapaty S, Sawai A, Scaltriti M, et al. 2011.AKTinhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19: 58-71
36. Chakrabarty A, Sanchez V, Kuba MG, et al. (2012). Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. PNAS 109: 2718-23
37. Garrett JT, Olivares MG, Rinehart C, et al. (2011). Transcriptional and posttranslational up-regulation of HER3 (ErbB3) compensates for inhibition of the HER2 tyrosine kinase. PNAS 108: 5021-26
38. Serra V, Scaltriti M, Prudkin L, et al. (2011). PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene 30: 2547-57
39. Rodrik-Outmezguine VS, Chandarlapaty S, Pagano NC, et al. (2011). mTOR kinase inhibition causes feedback-dependent biphasic regulation of AKT signaling. Cancer Discov. 1: 248-59
40. O'Reilly KE, Rojo F, She QB, et al. (2006). mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66: 1500-8
41. Majumder PK, Febbo PG, Bikoff R, et al. (2004). mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic andHIF-1-dependent pathways. Nat. Med. 10: 594-601
42. Bendell JC, Rodon J, Burris HA, et al. (2012). Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J. Clin. Oncol. 30: 282-90
43. Fox EM, Kuba MG, Miller TW, et al. (2013). Autocrine IGF-I/insulin receptor axis compensates for inhibition of AKT in ER-positive breast cancer cells with acquired resistance to estrogen deprivation. Breast Cancer Res. 15: R55
44. Tao JJ, Castel P, Radosevic-Robin N, et al. (2014). Antagonism of EGFR and HER3 enhances the response to inhibitors of the PI3K-Akt pathway in triple-negative breast cancer. Sci. Signal. 7: ra29
45. Garrett JT, Sutton CR, Kurupi R, et al. (2013). Combination of antibody that inhibits ligand-independent HER3 dimerization and a p110alpha inhibitor potently blocks PI3K signaling and growth of HER2+breast cancers. Cancer Res. 73: 6013-23
46. Elkabets M, Pazarentzos E, Juric D, et al. (2015). AXL mediates resistance to PI3Kalpha inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas. Cancer Cell 27: 533-46
47. Ellis MJ, Lin L, Crowder R, et al. (2010). Phosphatidyl-inositol-3-kinase alpha catalytic subunit mutation and response to neoadjuvant endocrine therapy for estrogen receptor positive breast cancer. Breast Cancer Res. Treat. 119: 379-90
48. Miller TW, Balko JM, Arteaga CL. (2011). Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J. Clin. Oncol. 29: 4452-61
49. Mayer IA, Abramson VG, Isakoff SJ, et al. (2014). Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 32: 1202-9
50. Miller TW, Hennessy BT, Gonzalez-Angulo AM, et al. (2010). Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J. Clin. Invest. 120: 2406-13
51. Crowder RJ, Phommaly C, Tao Y, et al. (2009). PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 69: 3955-62
52. Creighton CJ, Fu X, Hennessy BT, et al. (2010). Proteomic and transcriptomic profiling reveals a link between the PI3K pathway and lower estrogen-receptor (ER) levels and activity in ER+ breast cancer. Breast Cancer Res. 12: R40
53. Bosch A, Li Z, Bergamaschi A, et al. (2015). PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci. Transl. Med. 7: 283ra51
54. Miller TW, Balko JM, Fox EM, et al. (2011). ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov. 1: 338-51
55. Vora SR, Juric D, Kim N, et al. (2014). CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 26: 136-49
56. Juvekar A, Burga LN, Hu H, et al. (2012). Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2: 1048-63
57. Janku F, Wheler JJ, Westin SN, et al. (2012). PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J. Clin. Oncol. 30: 777-82
58. Ackermann TF, Hortnagl H, Wolfer DP, et al. (2008). Phosphatidylinositide dependent kinase deficiency increases anxiety and decreases GABA and serotonin abundance in the amygdala. Cell. Physiol. Biochem. 22: 735-44
59. Kalkman HO. (2006). The role of the phosphatidylinositide 3-kinase-protein kinase B pathway in schizophrenia. Pharmacol. Ther. 110: 117-34
60. Kurmasheva RT, Huang S, Houghton PJ. (2006). Predicted mechanisms of resistance to mTOR inhibitors. Br. J. Cancer 95: 955-60
61. Cancer Genome Atlas Research Network Collaborators. (2014). Comprehensive molecular profiling of lung adenocarcinoma. Nature 511: 543-50
62. Hudes G, Carducci M, Tomczak P, et al. (2007). Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N. Engl. J. Med. 356: 2271-81
63. Motzer RJ, Escudier B, Oudard S, et al. (2008). Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 372: 449-56
64. Baselga J, Campone M, Piccart M, et al. (2012). Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366: 520-29
65. Hortobagyi GN. (2015). Everolimus plus exemestane for the treatment of advanced breast cancer: a review of subanalyses from BOLERO-2. Neoplasia 17: 279-88
66. Loi S, Haibe-Kains B, Majjaj S, et al. (2010). PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor-positive breast cancer. PNAS 107: 10208-13
67. Krop IE, Johnston S, Mayer IA, et al. (2014). The FERGI phase II study of the PI3K inhibitor pictilisib (GDC-0941) plus fulvestrant versus fulvestrant plus placebo in patients with ER+, aromatase inhibitor (AI)-resistant advanced ormetastatic breast cancer-Part I results. In Proc. San Antonio Breast Cancer Symp. Abstr. S2-02
68. Serra V, Markman B, Scaltriti M, et al. (2008). NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 68: 8022-30
69. Chakrabarty A, Rexer BN, Wang SE, et al. (2010). H1047R phosphatidylinositol 3-kinase mutant enhances HER2-mediated transformation by heregulin production and activation of HER3. Oncogene 29: 5193-203
70. Eichhorn PJ, Gili M, Scaltriti M, et al. (2008). Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitorNVP-BEZ235. Cancer Res. 68: 9221-30
71. Hanker AB, Pfefferle AD, Balko JM, et al. (2013). Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. PNAS 110: 14372-77
72. Cizkova M, Susini A, Vacher S, et al. (2012). PIK3CA mutation impact on survival in breast cancer patients and in ERalpha, PR and ERBB2-based subgroups. Breast Cancer Res. 14: R28
73. Berns K, Horlings HM, Hennessy BT, et al. (2007). A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12: 395-402
74. Cizkova M, Dujaric ME, Lehmann-Che J, et al. (2013). Outcome impact of PIK3CA mutations in HER2-positive breast cancer patients treated with trastuzumab. Br. J. Cancer 108: 1807-9
75. Jensen JD, Knoop A, Laenkholm AV, et al. (2012). PIK3CA mutations, PTEN, and pHER2 expression and impact on outcome in HER2-positive early-stage breast cancer patients treated with adjuvant chemotherapy and trastuzumab. Ann. Oncol. 23: 2034-42
76. Baselga J, Cortes J, Im SA, et al. (2014). Biomarker analyses in CLEOPATRA: a phase III, placebocontrolled study of pertuzumab in human epidermal growth factor receptor 2-positive, first-linemetastatic breast cancer. J. Clin. Oncol. 32: 3753-61
77. Baselga J, Majewski I, Nuciforo PG, et al. (2013). PIK3CA mutations and correlation with pCR in the NeoALTTO trial (BIG 01-06). In Proc. Eur. Cancer Congr. Abstr. 1859
78. Loibl S, vonMinckwitz G, Schneeweiss A, et al. (2014). PIK3CA mutations are associated with lower rates of pathologic complete response to anti-human epidermal growth factor receptor 2 (her2) therapy in primary HER2-overexpressing breast cancer. J. Clin. Oncol. 32: 3212-20
79. Majewski IJ, Nuciforo P, Mittempergher L, et al. (2015). PIK3CA mutations are associated with decreased benefit to neoadjuvant human epidermal growth factor receptor 2-Targeted therapies in breast cancer. J. Clin. Oncol. 33: 1334-39
80. Gianni L, Bianchini G, Kiermaier A, et al (2011). Neoadjuvant pertuzumab (P) and trastuzumab (H): biomarker analyses of a 4-Arm randomized phase ii study (NeoSphere) in patients (pts) with HER2-positive breast cancer (BC).Presented at San Antonio Breast Cancer Symp., San Antonio, TX, Dec. 6-10
81. Contreras A, Herrera S, Wang T, et al. (2013). PIK3CA mutations and/or low PTEN predict resistance to combined anti-HER2 therapy with lapatinib and trastuzumab and without chemotherapy in TBCRC006, a neoadjuvant trial of HER2-positive breast cancer patients. Poster at San Antonio Breast Cancer Symp., San Antonio, TX, Dec. 10-14
82. Pogue-Geile KL, Song N, Jeong JH, et al. (2015). Intrinsic subtypes, PIK3CA mutation, and the degree of benefit from adjuvant trastuzumab in the NSABP B-31 trial. J. Clin. Oncol. 33: 1340-47
83. Lannutti BJ, Meadows SA, Herman SE, et al. (2011). CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood 117: 591-94
84. Herman SE, Gordon AL, Wagner AJ, et al. (2010). Phosphatidylinositol 3-kinase-delta inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 116: 2078-88
85. Meadows SA, Vega F, Kashishian A, et al. (2012). PI3Kdelta inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from themicroenvironment in cellular models of Hodgkin lymphoma. Blood 119: 1897-900
86. Keating MJ, Flinn I, Jain V, et al. (2002). Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 99: 3554-61
87. Lemery SJ, Zhang J, Rothmann MD, et al. (2010). US. Food and Drug Administration approval: ofatumumab for the treatment of patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab. Clin. Cancer Res. 16: 4331-38
88. Fischer K, Cramer P, Busch R, et al. (2011). Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J. Clin. Oncol. 29: 3559-66
89. Castillo JJ, Furman M, Winer ES. (2012). CAL-101: a phosphatidylinositol-3-kinase p110-delta inhibitor for the treatment of lymphoid malignancies. Expert Opin. Investig. Drugs 21: 15-22
90. Furman RR, Sharman JP, Coutre SE, et al. (2014). Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N. Engl. J. Med. 370: 997-1007