title: Development of PI3K inhibitors: lessons learned from early clinical trials.
abstract: The phosphatidylinositol 3-kinase (PI3K) pathway has an important role in cell metabolism, growth, migration, survival and angiogenesis. Drug development aimed at targetable genetic aberrations in the PI3K/AKT/mTOR pathway has been fomented by observations that alterations in this pathway induce tumour formation and that inappropriate PI3K signalling is a frequent occurrence in human cancer. Many of the agents developed have been evaluated in early stage clinical trials. This Review focuses on early clinical and translational data related to inhibitors of the PI3K/AKT/mTOR pathway, as these data will likely guide the further clinical development of such agents. We review data from those trials, delineating the safety profile of the agents--whether observed sequelae could be mechanism-based or off-target effects--and drug efficacy. We describe predictive biomarkers explored in clinical trials and preclinical mechanisms of resistance. We also discuss key unresolved translational questions related to the clinical development of inhibitors of the PI3K/AKT/mTOR pathway and propose designs for biomarker-driven trials to address those issues.
authors: Medical Oncology Department, Vall d'Hebrón University Hospital, Universitat Autònoma de Barcelona, Passeig Vall d'Hebron 119, Edifici Maternoinfantil Planta 14, 08035 Barcelona, Spain. jrodon@vhio.net
authors: Jordi
authors: J
authors: Rodon
authors: Rodrigo
authors: R
authors: Dienstmann
authors: Violeta
authors: V
authors: Serra
authors: Josep
authors: J
authors: Tabernero
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers; D002986:Clinical Trials as Topic; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D013379:Substrate Specificity; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D007527:Isoenzymes; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C494918:AKT1 protein, human
references: J Clin Oncol. 2010 Feb 20;28(6):1075-83
references: 20085938
references: Oncogene. 2011 Jun 2;30(22):2547-57
references: 21278786
references: Nat Med. 2011 Aug 07;17(9):1116-20
references: 21822287
references: Mol Cell. 2008 Apr 25;30(2):203-13
references: 18439899
references: N Engl J Med. 2009 Sep 3;361(10):947-57
references: 19692680
references: J Clin Oncol. 2012 Mar 10;30(8):765-6
references: 22271482
references: J Clin Oncol. 2009 Jun 1;27(16):2697-704
references: 19380450
references: J Clin Oncol. 2012 Aug 10;30(23):2919-28
references: 22778315
references: Curr Drug Saf. 2009 May;4(2):143-54
references: 19442108
references: Nat Chem Biol. 2011 Sep 25;7(11):787-93
references: 21946274
references: Cancer Discov. 2012 Jan;2(1):56-67
references: 22328975
references: J Cell Biochem. 2012 Mar;113(3):784-91
references: 22020918
references: Oncotarget. 2011 Apr;2(4):321-8
references: 21487159
references: Clin Cancer Res. 2012 Jul 15;18(14):3901-11
references: 22586300
references: Cancer Cell. 2009 Jul 7;16(1):21-32
references: 19573809
references: Anticancer Res. 2012 Feb;32(2):445-52
references: 22287731
references: Oncologist. 2011;16(12):1729-40
references: 22135123
references: Cancer Res. 2009 May 1;69(9):3955-62
references: 19366795
references: Curr Opin Cell Biol. 2009 Apr;21(2):199-208
references: 19200708
references: Cancer Res. 2010 Feb 1;70(3):1164-72
references: 20103642
references: FEBS Lett. 2005 Sep 26;579(23):5123-8
references: 16150444
references: Curr Top Microbiol Immunol. 2010;347:189-208
references: 20593313
references: Nature. 2011 Jun 29;474(7353):609-15
references: 21720365
references: J Clin Oncol. 2009 Aug 10;27(23):3822-9
references: 19581539
references: Clin Cancer Res. 2012 Apr 15;18(8):2316-25
references: 22261800
references: J Clin Invest. 2008 Sep;118(9):3065-74
references: 18725988
references: N Engl J Med. 2011 Feb 10;364(6):514-23
references: 21306238
references: Clin Cancer Res. 2010 Jul 15;16(14):3670-83
references: 20453058
references: J Clin Invest. 2011 Apr;121(4):1231-41
references: 21490404
references: Cancer Chemother Pharmacol. 2006 Oct;58(4):444-50
references: 16485116
references: J Clin Oncol. 2009 Jun 1;27(16):2630-7
references: 19380449
references: Int J Oncol. 2012 Mar;40(3):639-44
references: 22200790
references: Proc Natl Acad Sci U S A. 2009 Dec 29;106(52):22299-304
references: 20007781
references: Proc Natl Acad Sci U S A. 2009 Oct 27;106(43):18351-6
references: 19805051
references: Proc Natl Acad Sci U S A. 2011 Sep 13;108(37):E699-708
references: 21876152
references: Cell. 2006 May 19;125(4):733-47
references: 16647110
references: Nature. 2012 Jun 20;486(7403):405-9
references: 22722202
references: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13057-62
references: 18755892
references: Mol Cancer Ther. 2011 Mar;10(3):558-65
references: 21216929
references: Clin Cancer Res. 2011 May 15;17(10):3193-203
references: 21325073
references: Cancer Res. 2002 Feb 15;62(4):1087-92
references: 11861387
references: N Engl J Med. 2011 Jun 30;364(26):2507-16
references: 21639808
references: Science. 2009 May 22;324(5930):1029-33
references: 19460998
references: PLoS One. 2011;6(9):e25132
references: 21966435
references: Cancer. 2010 Sep 15;116(18):4256-65
references: 20549832
references: J Clin Oncol. 2012 Jan 20;30(3):282-90
references: 22162589
references: Cancer Cell. 2011 May 17;19(5):575-86
references: 21575859
references: Proc Natl Acad Sci U S A. 2008 Feb 19;105(7):2652-7
references: 18268322
references: BMC Med. 2012 Dec 11;10:161
references: 23232172
references: Clin Cancer Res. 2012 Jun 15;18(12):3462-9
references: 22421194
references: Nat Rev Cancer. 2011 Feb;11(2):85-95
references: 21258394
references: Cancer Discov. 2012 Aug;2(8):666-9
references: 22886659
references: Cancer Discov. 2011 Aug;1(3):248-59
references: 22140653
references: Nat Rev Clin Oncol. 2012 Apr 03;9(6):359-66
references: 22473105
references: Clin Cancer Res. 2015 Feb 15;21(4):730-8
references: 25500057
references: Proc Natl Acad Sci U S A. 2008 Nov 11;105(45):17414-9
references: 18955708
references: Clin Cancer Res. 2011 May 15;17(10):3332-40
references: 21257723
references: Cancer Discov. 2012 Jan;2(1):16-8
references: 22585163
references: Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3041-6
references: 18287029
references: Biochem J. 2008 Oct 1;415(1):97-110
references: 18498248
references: Nature. 2010 Sep 30;467(7315):596-9
references: 20823850
references: Nat Med. 2008 Dec;14(12):1351-6
references: 19029981
references: Cancer Res. 2006 Feb 1;66(3):1500-8
references: 16452206
references: Nat Med. 2012 Jun;18(6):892-901
references: 22610277
references: Cell. 2007 Jun 29;129(7):1261-74
references: 17604717
references: J Clin Oncol. 2012 Aug 10;30(23):2861-8
references: 22753904
references: Nature. 2012 Jul 18;487(7407):330-7
references: 22810696
references: Breast Cancer Res. 2011;13(6):224
references: 22114931
references: Mol Cell Biol. 2000 May;20(10):3558-67
references: 10779345
references: Mol Cancer Ther. 2003 Nov;2(11):1093-103
references: 14617782
references: Nature. 2008 Oct 23;455(7216):1061-8
references: 18772890
references: J Clin Oncol. 2011 Dec 10;29(35):4688-95
references: 22025163
references: N Engl J Med. 2007 May 31;356(22):2271-81
references: 17538086
references: N Engl J Med. 2012 Feb 9;366(6):520-9
references: 22149876
references: J Cell Physiol. 2012 Jul;227(7):2818-21
references: 21938729
references: Nature. 2006 May 18;441(7091):366-70
references: 16625210
references: N Engl J Med. 2002 Aug 15;347(7):472-80
references: 12181401
references: Nat Rev Genet. 2006 Aug;7(8):606-19
references: 16847462
references: Oncogene. 2011 Jul 21;30(29):3222-33
references: 21358673
references: Cancer Cell. 2011 Jan 18;19(1):58-71
references: 21215704