The PI3K pathway as drug target in human cancer

Journal of Clinical Oncology

Volumn 28, Issue 6, 2010, Pages 1075-1083

  Courtney, Kevin D ^a   Corcoran, Ryan B ^a   Engelman, Jeffrey A ^a  

^a NONE

Author keywords

[No Author keywords available]

Indexed keywords

1 (1 CYANO 1 METHYLETHYL) 3 METHYL 8 (3 QUINOLINYL)IMIDAZO[4,5 C]QUINOLIN 2(1H,3H) ONE; 2 (1H INDAZOL 4 YL) 6 (4 METHANESULFONYL 1 PIPERAZINYLMETHYL) 4 MORPHOLINOTHIENO[3,2 D]PYRIMIDINE; 4 DIALLYLAMINOMETHYLENE 1,3,4,7,10,11,12,13,14,15,16,17 DODECAHYDRO 6 HYDROXY 1 METHOXYMETHYL 10,13 DIMETHYL 3,7,17 TRIOXO 2 OXACYCLOPENTA[A]PHENANTHREN 11 YL ACETATE; [1 (4 OXO 8 PHENYL 4H 1 BENZOPYRAN 2 YL)MORPHOLINIO]METHOXYSUCCINYLARGINYLGLYCYLASPARTYLSERINE ACETATE; GEFITINIB; IMATINIB; INSULIN; MAMMALIAN TARGET OF RAPAMYCIN INHIBITOR; MK 2206; NVP BGT 226; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B; PROTEIN KINASE B INHIBITOR; PROTEIN P110; RAS PROTEIN; TYROSINE KINASE RECEPTOR; UNCLASSIFIED DRUG; WAY 600; WYE 354; WYE 687; ANTINEOPLASTIC AGENT;

CANCER GROWTH; CANCER THERAPY; CELL PROLIFERATION; CELL SURVIVAL; DRUG TARGETING; GENE MUTATION; GLUCOSE HOMEOSTASIS; HUMAN; INSULIN RESISTANCE; NEOPLASM; NONHUMAN; ONCOGENE; PHARMACODYNAMICS; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; TOXICITY; TREATMENT OUTCOME; TUMOR CELL; ANIMAL; DRUG ANTAGONISM; ENZYMOLOGY; METABOLISM;

1-PHOSPHATIDYLINOSITOL 3-KINASE; ANIMALS; ANTINEOPLASTIC AGENTS; HUMANS; NEOPLASMS;

EID: 77949881462     PISSN: 0732183X     EISSN: 15277755     Source Type: Journal    
DOI: 10.1200/JCO.2009.25.3641     Document Type: Review

References (108)

1. Jia S, Roberts TM, Zhao JJ: Should individual PI3 kinase isoforms be targeted in cancer? Curr Opin Cell Biol 21:199-208, 2009
2. Kaplan DR, Whitman M, Schaffhausen B, et al: Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell 50:1021-1029, 1987
3. Sugimoto Y, Whitman M, Cantley LC, et al: Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc Natl Acad Sci U S A 81: 2117-2121, 1984 (Pubitemid 14146614)
4. Whitman M, Kaplan DR, Schaffhausen B, et al: Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315:239-242, 1985 (Pubitemid 15064453)
5. Engelman JA, Luo J, Cantley LC: The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606-619, 2006 (Pubitemid 44100518)
6. Samuels Y, Wang Z, Bardelli A, et al: High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554, 2004 (Pubitemid 38541907)
7. Yuan TL, Cantley LC: PI3K pathway alterations in cancer: Variations on a theme. Oncogene 27:5497-5510, 2008
8. Katso R, Okkenhaug K, Ahmadi K, et al: Cellular function of phosphoinositide 3-kinases: Implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 17:615-675, 2001 (Pubitemid 33096187)
9. Ikenoue T, Kanai F, Hikiba Y, et al: Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562-4567, 2005 (Pubitemid 40740791)
10. Mizoguchi M, Nutt CL, Mohapatra G, et al: Genetic alterations of phosphoinositide 3-kinase subunit genes in human glioblastomas. Brain Pathol 14:372-377, 2004 (Pubitemid 39524966)
11. Philp AJ, Campbell IG, Leet C, et al: The phosphatidylinositol 3′-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 61:7426-7429, 2001 (Pubitemid 32995029)
12. Samuels Y, Velculescu VE: Oncogenic mutations of PIK3CA in human cancers. Cell Cycle 3:1221-1224, 2004 (Pubitemid 40268595)
13. Kang S, Denley A, Vanhaesebroeck B, et al: Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proc Natl Acad Sci U S A 103:1289-1294, 2006
14. Skolnik EY, Margolis B, Mohammadi M, et al: Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 65:83-90, 1991 (Pubitemid 121001216)
15. Zhao L, Vogt PK: Class I PI3K in oncogenic cellular transformation. Oncogene 27:5486-5496, 2008
16. Carpenter CL, Auger KR, Chanudhuri M, et al: Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol Chem 268:9478-9483, 1993 (Pubitemid 23146000)
17. Shaw RJ, Cantley LC: Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441: 424-430, 2006
18. Cantley LC: The phosphoinositide 3-kinase pathway. Science 296:1655-1657, 2002
19. Alessi DR, James SR, Downes CP, et al: Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261-269, 1997 (Pubitemid 27176852)
20. Currie RA, Walker KS, Gray A, et al: Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J 337:575-583, 1999
21. Majumder PK, Sellers WR: Akt-regulated pathways in prostate cancer. Oncogene 24:7465-7474, 2005 (Pubitemid 41637986)
22. Duronio V: The life of a cell: Apoptosis regulation by the PI3K/PKB pathway. Biochem J 415: 333-344, 2008
23. Hresko RC, Mueckler M: mTOR.RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes. J Biol Chem 280:40406-40416, 2005 (Pubitemid 41780527)
24. Sarbassov DD, Ali SM, Sengupta S, et al: Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22:159-168, 2006
25. Sarbassov DD, Guertin DA, Ali SM, et al: Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098-1101, 2005 (Pubitemid 40262113)
26. Carracedo A, Pandolfi PP: The PTEN-PI3K pathway: Of feedbacks and cross-talks. Oncogene 27:5527-5541, 2008
27. Harrington LS, Findlay GM, Gray A, et al: The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166:213-223, 2004 (Pubitemid 38988774)
28. O'Reilly KE, Rojo F, She QB, et al: mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500-1508, 2006 (Pubitemid 43259931)
29. Ma WW, Adjei AA: Novel agents on the horizon for cancer therapy. CA Cancer J Clin 59:111-137, 2009
30. Meric-Bernstam F, Gonzalez-Angulo AM: Targeting the mTOR signaling network for cancer therapy. J Clin Oncol 27:2278-2287, 2009
31. Luo J, Sobkiw CL, Hirshman MF, et al: Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. Cell Metab 3:355-366, 2006
32. Cho H, Mu J, Kim JK, et al: Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292:1728-1731, 2001 (Pubitemid 32506248)
33. Taniguchi CM, Tran TT, Kondo T, et al: Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN. Proc Natl Acad Sci U S A 103:12093-12097, 2006 (Pubitemid 44215816)
34. Ueki K, Yballe CM, Brachmann SM, et al: Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci U S A 99:419-424, 2002 (Pubitemid 34060376)
35. Jia S, Liu Z, Zhang S, et al: Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776-779, 2008
36. Knight ZA, Gonzalez B, Feldman ME, et al: A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125:733-747, 2006
37. Bader AG, Kang S, Vogt PK: Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci U S A 103:1475-1479, 2006 (Pubitemid 43191190)
38. Li J, Yen C, Liaw D, et al: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275:1943-1947, 1997
39. Shayesteh L, Lu Y, Kuo WL, et al: PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21:99-102, 1999 (Pubitemid 29036292)
40. Shoji K, Oda K, Nakagawa S, et al: The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br J Cancer 101:145-148, 2009
41. Steck PA, Pershouse MA, Jasser SA, et al: Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet 15:356-362, 1997 (Pubitemid 27147102)
42. García JM, Silva J, Peña C, et al: Promoter methylation of the PTEN gene is a common molecular change in breast cancer. Genes Chromosomes Cancer 41:117-124, 2004 (Pubitemid 39096737)
43. Goel A, Arnold CN, Niedzwiecki D, et al: Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res 64:3014-3021, 2004 (Pubitemid 38581399)
44. Berns K, Horlings HM, Hennessy BT, et al: A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12:395-402, 2007 (Pubitemid 47539306)
45. Sun X, Huang J, Homma T, et al: Genetic alterations in the PI3K pathway in prostate cancer. Anticancer Res 29:1739-1743, 2009
46. Byun DS, Cho K, Ryu BK, et al: Frequent monoallelic deletion of PTEN and its reciprocal association with PIK3CA amplification in gastric carcinoma. Int J Cancer 104:318-327, 2003 (Pubitemid 36249814)
47. Campbell IG, Russell SE, Choong DY, et al: Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678-7681, 2004 (Pubitemid 39446895)
48. Ma YY, Wei SJ, Lin YC, et al: PIK3CA as an oncogene in cervical cancer. Oncogene 19:2739-2744, 2000
49. Rácz A, Brass N, Heckel D, et al: Expression analysis of genes at 3q26-q27 involved in frequent amplification in squamous cell lung carcinoma. Eur J Cancer 35:641-646, 1999 (Pubitemid 29192975)
50. Carpten JD, Faber AL, Horn C, et al: A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439-444, 2007 (Pubitemid 47123510)
51. Davies MA, Stemke-Hale K, Tellez C, et al: A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer 99:1265-1268, 2008
52. Parsons DW, Wang TL, Samuels Y, et al: Colorectal cancer: Mutations in a signalling pathway. Nature 436:792, 2005 (Pubitemid 41160630)
53. Cheng JQ, Godwin AK, Bellacosa A, et al: AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci U S A 89:9267-9271, 1992
54. Cheng JQ, Ruggeri B, Klein WM, et al: Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A 93:3636-3641, 1996 (Pubitemid 26127592)
55. Bellacosa A, de Feo D, Godwin AK, et al: Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer 64:280-285, 1995
56. Haas-Kogan D, Shalev N, Wong M, et al: Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol 8:1195-1198, 1998 (Pubitemid 28494720)
57. Myers MP, Pass I, Batty IH, et al: The lipid phosphatase activity of PTEN is critical for its tumor suppressor function. Proc Natl Acad Sci U S A 95:13513-13518, 1998 (Pubitemid 28523003)
58. Han SY, Kato H, Kato S, et al: Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. Cancer Res 60:3147-3151, 2000 (Pubitemid 30407908)
59. Liaw D, Marsh DJ, Li J, et al: Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16:64-67, 1997 (Pubitemid 27198157)
60. Huang CH, Mandelker D, Schmidt-Kittler O, et al: The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744-1748, 2007 (Pubitemid 350274378)
61. Miled N, Yan Y, Hon WC, et al: Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317: 239-242, 2007 (Pubitemid 47076198)
62. Engelman JA, Mukohara T, Zejnullahu K, et al: Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest 116:2695-2706, 2006 (Pubitemid 44511633)
63. Isakoff SJ, Engelman JA, Irie HY, et al: Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res 65:10992-11000, 2005 (Pubitemid 41713369)
64. Zhao JJ, Liu Z, Wang L, et al: The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci U S A 102:18443-18448, 2005 (Pubitemid 43011245)
65. Engelman JA, Chen L, Tan X, et al: Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351-1356, 2008
66. Shekar SC, Wu H, Fu Z, et al: Mechanism of constitutive phosphoinositide 3-kinase activation by oncogenic mutants of the p85 regulatory subunit. J Biol Chem 280:27850-27855, 2005 (Pubitemid 41076901)
67. Engelman JA, Settleman J: Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr Opin Genet Dev 18:73-79, 2008 (Pubitemid 351694445)
68. Eichhorn PJ, Gili M, Scaltriti M, et al: Phosphatidylinositol 3-kinase hyperactivation results in lapatinib resistance that is reversed by the mTOR/phosphatidylinositol 3-kinase inhibitor NVP-BEZ235. Cancer Res 68:9221-9230, 2008
69. Holbro T, Beerli RR, Maurer F, et al: The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A 100:8933-8938, 2003 (Pubitemid 36899201)
70. Moasser MM, Basso A, Averbuch SD, et al: The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. Cancer Res 61:7184-7188, 2001 (Pubitemid 32946513)
71. Mellinghoff IK, Wang MY, Vivanco I, et al: Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med 353:2012-2024, 2005 (Pubitemid 41609094)
72. Stommel JM, Kimmelman AC, Ying H, et al: Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science 318:287-290, 2007 (Pubitemid 47574858)
73. Lim KH, Counter CM: Reduction in the requirement of oncogenic Ras signaling to activation of PI3K/AKT pathway during tumor maintenance. Cancer Cell 8:381-392, 2005
74. Pacold ME, Suire S, Perisic O, et al: Crystal structure and functional analysis of Ras binding to its effector phosphoinositide 3-kinase gamma. Cell 103:931-943, 2000
75. Rodriguez-Viciana P, Warne PH, Khwaja A, et al: Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 89:457-467, 1997 (Pubitemid 27220890)
76. Gupta S, Ramjaun AR, Haiko P, et al: Binding of ras to phosphoinositide 3-kinase p110alpha is required for ras-driven tumorigenesis in mice. Cell 129: 957-968, 2007 (Pubitemid 46802703)
77. Ihle NT, Lemos R Jr, Wipf P, et al: Mutations in the phosphatidylinositol-3-kinase pathway predict for antitumor activity of the inhibitor PX-866 whereas oncogenic Ras is a dominant predictor for resistance. Cancer Res 69:143-150, 2009
78. Hickey FB, Cotter TG: BCR-ABL regulates phosphatidylinositol 3-kinase-p110gamma transcription and activation and is required for proliferation and drug resistance. J Biol Chem 281:2441-2450, 2006 (Pubitemid 43845703)
79. Sujobert P, Bardet V, Cornillet-Lefebvre P, et al: Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106:1063-1066, 2005 (Pubitemid 41076455)
80. Salmena L, Carracedo A, Pandolfi PP: Tenets of PTEN tumor suppression. Cell 133:403-414, 2008 (Pubitemid 351622014)
81. Wee S, Wiederschain D, Maira SM, et al: PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci U S A 105:13057-13062, 2008
82. Chiorean EG, Mahadevan D, Harris WB, et al: Phase I evaluation of SF1126, a vascular targeted PI3K inhibitor, administered twice weekly IV in patients with refractory solid tumors. J Clin Oncol 27:122s, 2009 (suppl; abstr 2558)
83. LoRusso P, Markman B, Tabernero J, et al: A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics of XL765, a PI3K/TORC1/TORC2 inhibitor administered orally to patients (pts) with advanced solid tumors. J Clin Oncol 27:146s, 2009 (suppl; abstr 3502)
84. Jimeno A, Hong DS, Hecker S, et al: Phase I trial of PX-866, a novel phosphoinositide-3-kinase (PI-3K) inhibitor. J Clin Oncol 27:156s, 2009 (suppl; abstr 3542)
85. Shapiro G, Kwak E, Baselga J, et al: Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors. J Clin Oncol 27:146s, 2009 (suppl; abstr 3500)
86. Markman B, Atzori F, Pérez-Garcia J, et al: Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann Oncol doi: 10.1093/annonc/mdp347 [epub ahead of print on August 27, 2009]
87. Wagner AJ, Von Hoff DH, LoRusso PM, et al: A first-in-human phase I study to evaluate the pan-PI3K inhibitor GDC-0941 administered QD or BID in patients with advanced solid tumors. J Clin Oncol 27:146s, 2009 (suppl; abstr 3501)
88. Flinn IW, Byrd JC, Furman RR, et al: Preliminary evidence of clinical activity in a phase I study of CAL-101, a selective inhibitor of the p1108 isoform of phosphatidylinositol 3-kinase (PI3K), in patients with select hematologic malignancies. J Clin Oncol 27:156s, 2009 (suppl; abstr 3543)
89. Tolcher AW, Yap TA, Fearen I, et al: A phase I study of MK-2206, an oral potent allosteric Akt inhibitor (Akti), in patients (pts) with advanced solid tumor (ST). J Clin Oncol 27:146s, 2009 (suppl; abstr 3503)
90. Garcia-Echeverria C, Sellers WR: Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27:5511-5526, 2008
91. Garlich JR, De P, Dey N, et al: A vascular targeted pan phosphoinositide 3-kinase inhibitor prodrug, SF1126, with antitumor and antiangiogenic activity. Cancer Res 68:206-215, 2008 (Pubitemid 351380122)
92. Maira SM, Stauffer F, Brueggen J, et al: 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, 2008
93. Serra V, Markman B, Scaltriti M, et al: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68:8022-8030, 2008
94. Crowder RJ, Phommaly C, Tao Y, et al: PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res 69:3955-3962, 2009
95. Blois J, Yuan H, Smith A, et al: Slow self-activation enhances the potency of viridin prodrugs. J Med Chem 51:4699-4707, 2008
96. Howes AL, Chiang GG, Lang ES, et al: The phosphatidylinositol 3-kinase inhibitor, PX-866, is a potent inhibitor of cancer cell motility and growth in three-dimensional cultures. Mol Cancer Ther 6:2505-2514, 2007 (Pubitemid 47480416)
97. Smith A, Blois J, Yuan H, et al: The antiproliferative cytostatic effects of a self-activating viridin prodrug. Mol Cancer Ther 8:1666-1675, 2009
98. Ihle NT, Paine-Murrieta G, Berggren MI, et al: The phosphatidylinositol- 3-kinase inhibitor PX-866 overcomes resistance to the epidermal growth factor receptor inhibitor gefitinib in A-549 human nonsmall cell lung cancer xenografts. Mol Cancer Ther 4:1349-1357, 2005
99. Chen JS, Zhou LJ, Entin-Meer M, et al: Characterization of structurally distinct, isoform-selective phosphoinositide 3′-kinase inhibitors in combination with radiation in the treatment of glioblastoma. Mol Cancer Ther 7:841-850, 2008 (Pubitemid 351551037)
100. Torbett NE, Luna-Moran A, Knight ZA, et al: A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. Biochem J 415:97-110, 2008
101. She QB, Chandarlapaty S, Ye Q, et al: Breast tumor cells with PI3K mutation or HER2 amplification are selectively addicted to Akt signaling. PLoS One 3:e3065, 2008
102. Vasudevan KM, Barbie DA, Davies MA, et al: AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16:21-32, 2009
103. Guertin DA, Sabatini DM: The pharmacology of mTOR inhibition. Sci Signal 2:pe24, 2009
104. Yu K, Toral-Barza L, Shi C, et al: Biochemical, cellular, and in vivo activity of novel ATP-competitive and selective inhibitors of the mammalian target of rapamycin. Cancer Res 69:6232-6240, 2009
105. Feldman ME, Apsel B, Uotila A, et al: Activesite inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7:e38, 2009
106. Thoreen CC, Kang SA, Chang JW, et al: An ATP-competitive mammalian target of rapamycin inhibitor reveals rapamycin-resistant functions of mTORC1. J Biol Chem 284:8023-8032, 2009
107. Junttila TT, Akita RW, Parsons K, et al: Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell 15:429-440, 2009
108. Faber AC, Li D, Song Y, et al: Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci U S A 106:19503-19508, 2009