Intermittent high-dose scheduling of AZD8835, a novel selective inhibitor of PI3Ka and PI3Kd, demonstrates treatment strategies for PIK3CA-dependent breast cancers

Molecular Cancer Therapeutics

Volumn 15, Issue 5, 2016, Pages 877-889

  Hudson, Kevin ^a   Hancox, Urs J ^a   Trigwell, Cath ^a   McEwen, Robert ^a   Polanska, Urszula M ^a   Nikolaou, Myria ^a   Gutierrez, Pablo Morentin ^a   Avivar Valderas, Alvaro ^a   Delpuech, Oona ^a   Dudley, Phillippa ^a   Hanson, Lyndsey ^a   Ellston, Rebecca ^a   Jones, Alys ^a   Cumberbatch, Marie ^a   Cosulich, Sabina C ^a   Ward, Lara ^a   Cruzalegui, Francisco ^a   Green, Stephen ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; AZD 8835; AZD 9496; CASPASE 3; CYCLIN DEPENDENT KINASE 4; CYCLIN DEPENDENT KINASE 6; ESTROGEN RECEPTOR; FULVESTRANT; MAMMALIAN TARGET OF RAPAMYCIN; PALBOCICLIB; PHOSPHATIDYLINOSITOL 3 KINASE; PHOSPHATIDYLINOSITOL 3 KINASE ALPHA; PHOSPHATIDYLINOSITOL 3 KINASE BETA; PHOSPHATIDYLINOSITOL 3 KINASE GAMMA; PHOSPHATIDYLINOSITOL 3 KINASE INHIBITOR; PROTEIN KINASE B; UNCLASSIFIED DRUG; VISTUSERTIB; AZD8835; ISOENZYME; OXADIAZOLE DERIVATIVE; PIPERIDINE DERIVATIVE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTINEOPLASTIC ACTIVITY; ANTIPROLIFERATIVE ACTIVITY; ARTICLE; BREAST CANCER; BREAST CANCER CELL LINE; CANCER RESISTANCE; CELL CYCLE; CELL PROLIFERATION; CONTROLLED STUDY; DRUG EFFICACY; DRUG MEGADOSE; DRUG POTENCY; DRUG POTENTIATION; DRUG SELECTIVITY; DRUG SENSITIVITY; ENZYME INHIBITION; EX VIVO STUDY; FEMALE; GENE EXPRESSION; HUMAN; HUMAN CELL; IC50; MCF 7 CELL LINE; MONOTHERAPY; MORNING DOSAGE; MOUSE; NONHUMAN; PRIORITY JOURNAL; SIGNAL TRANSDUCTION; TUMOR REGRESSION; TUMOR XENOGRAFT; WESTERN BLOTTING; ANIMAL; ANTAGONISTS AND INHIBITORS; APOPTOSIS; BREAST NEOPLASMS; CELL DEATH; CHEMISTRY; CLUSTER ANALYSIS; DISEASE MODEL; DOSE RESPONSE; DRUG EFFECTS; DRUG SCREENING; GENE EXPRESSION PROFILING; GENETICS; METABOLISM; PATHOLOGY; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; APOPTOSIS; BREAST NEOPLASMS; CELL DEATH; CELL LINE, TUMOR; CELL PROLIFERATION; CLUSTER ANALYSIS; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; FEMALE; GENE EXPRESSION PROFILING; HUMANS; ISOENZYMES; MICE; OXADIAZOLES; PHOSPHATIDYLINOSITOL 3-KINASES; PIPERIDINES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84969524541     PISSN: 15357163     EISSN: 15388514     Source Type: Journal    
DOI: 10.1158/1535-7163.MCT-15-0687     Document Type: Article

References (49)

1. Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer 2015;1:7-24.
2. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 2004;304:554.
3. Samuels Y, Diaz LAJr, Schmidt-Kittler O, Cummins JM,Delong L, Cheong I, et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 2005;7:561-73.
4. Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 2006;7: 606-19.
5. Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 2008;27:5486-96.
6. Koboldt DC, Fulton RS, McLellan MD, Schmidt H, Kalicki-Veizer JM, et al. Comprehensive molecular portraits of human breast tumors. Nature 2012;490:61-70.
7. Hammerman PS, Lawrence MS, Voet D, Jing R, Cibulskis K, Sivachenko A, et al. Comprehensive genomic characterization of squamous cell lung cancers. Nature 2012;489:519-25.
8. Walter V, Yin X, Wilkerson MD, Cabanski CR, Zhao N, Du Y, et al. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. PLoS ONE 2013;8:e56823.
9. Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, et al. The phosphatidylinositol 30-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 2001;61:7426-9.
10. Rodon J, Dienstmann R, Serra V, Tabernero J. Development of PI3K inhibitors: lessons learned from early clinical trials. Nat Rev Clin Oncol 2013;10:143-53.
11. Fruman DA, Rommel C. PI3K and cancer: lessons, challenges and opportunities. Nat Rev Drug Discov 2014;13:140-56.
12. Juric D, Argiles G, Burris HA, Gonzalez-Angulo AM, Saura C, Quadt C, et al. Phase I study of BYL719, an a-specific PI3K inhibitor, in patients with PIK3CA mutant advanced solid tumors: preliminary efficacy and safety in patients with PIK3CA mutant ER-positive (ER+) metastatic breast cancer (MBC) [Abstracts]. In proceedings of Thirty-Fifth Annual CTRCAACR San Antonio Breast Cancer Symposium Dec 48, 2012; San Antonio, TX. Abstract P6-10-07.
13. Gonzalez-Angulo AM, Juric D, Gargilés G, Schellens JHM, Burris HA, Berlin J, et al. Safety, pharmacokinetics, and preliminary activity of the a-specific PI3K inhibitor BYL719: results from the first-in-human study. J Clin Oncol 31, 2013(suppl; Abstract 2531).
14. Juric D, Krop I, Ramanathan RK, Xiao J, Sanabria S, Wilson TR, et al. GDC-0032, a beta isoform-sparing PI3K inhibitor: Results of a first-in-human phase Ia dose escalation study. Cancer Res 2013;73(8 Suppl):Abstract LB-64.
15. Juric D, Saura C, Cervantes A, Kurkjian C, Patel MR, Sachdev J, et al. Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer. Cancer Res 2013;73(24 Suppl):Abstract PD1-3.
16. Juric D, Soria J-C, Sharma S, Banerji U, Azaro A, Desai J, et al. A phase 1b dose-escalation study of BYL719 plus binimetinib (MEK162) in patients with selected advanced solid tumors. J Clin Oncol 32, 2014(5S suppl: Abstract 9051).
17. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66:1500-8.
18. Chandarlapaty S, Sawai A, Scaltriti M, Rodrik-Outmezguine V, Grbovic-Huezo O, Serra V, et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 2011;19: 58-71.
19. Barlaam B, Cosulich S, Delouvrié B, Ellston R, Fitzek M, Germain H, et al. Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Ka and PI3Kd for the treatment of cancers. Bioorg Med Chem Lett 2015;25; 5155-62.
20. Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, et al. Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation ofmonotherapy activity with genetic background. Mol Cancer Ther 2012;11:873-87.
21. Bracken AP, Ciro M, Cocito A, Helin K. E2F target genes: unraveling the biology. Trends Biochem Sci 2004;29:409-17.
22. Lam EW, Brosens JJ, Gomes AR, Koo CY. Forkhead box proteins: tuning forks for transcriptional harmony. Nat Rev Cancer 2013;13:482-95.
23. Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A, et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med 2015; 7:283ra51.
24. Ni J, Liu Q, Xie S, Carlson C, Von T, Vogel K, et al. Functional characterization of an isoform-selective inhibitor of PI3K-p110b as a potential anticancer agent. Cancer Discov 2012;2:425-33.
25. Garnett MJ, Edelman EJ, Heidorn SJ, Greenman CD, Dastur A, Lau KW, et al. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012;483:570-5.
26. Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, LiuM, et al. Characterization of the novel and specific PI3Ka inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther 2014;13:1117-29.
27. Will M, Qin AC, Toy W, Yao Z, Rodrik-Outmezguine V, Schneider C, et al. Rapid induction of apoptosis by PI3K inhibitors is dependent upon their transient inhibition of RAS-ERK signaling. Cancer Discov 2014;4:334-47.
28. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, WilliamsO, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 2006;125:733-47.
29. Sopasakis VR, Liu P, Suzuki R, Kondo T,Winnay J, Tran TT, et al. Specific roles of the p110a isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab 2010;11: 220-30.
30. Jänicke RU, Sprengart ML, Wati MR, Porter AG. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J Biol Chem 1998;273:9357-60.
31. Rogakou EP, Nieves-Neira W, Boon C, Pommier Y, Bonner WM. Initiation ofDNAfragmentation during apoptosis induces phosphorylation ofH2AX histone at serine 139. J Biol Chem 2000;275:9390-5.
32. Morris C,Wakeling A. Fulvestrant ('Faslodex') - a new treatment option for patients progressing on prior endocrine therapy. Endocr Relat Cancer 2002;9:267-76.
33. Weir H, Lawson M, Callis R, Hulse M, Tonge M, Davies G, et al. Discovery and pre-clinical pharmacology of AZD9496: an oral, selective estrogen receptor down regulator (SERD) [abstract]. In proceedings of AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA ACCR. Abstract DDT01-03.
34. Fry DW, Harvey PJ, Keller PR, Elliott WL, MeadeM, Trachet E, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3: 1427-38.
35. Guichard SM, Curwen J, Bihani T, D'Cruz CM, Yates JW, Grondine M, et al. AZD2014, an inhibitor of mTORC1 and mTORC2, is highly effective in ER+ breast cancer when administered using intermittent or continuous schedules. Mol Cancer Ther 2015;14:2508-18.
36. Cosera KR, Wittner BS, Rosenthal NF, Collins SC, Melas A, Smith SL, et al. Antiestrogen-resistant subclones of MCF-7 human breast cancer cells are derived from a common monoclonal drug-resistant progenitor. PNAS 2009;106:14536-41.
37. Miller TW, Balko JM, Fox EM, Ghazoui Z, Dunbier A, Anderson H, et al. ERa-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 2011;1:338-51.
38. Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 2011;29:4452-61.
39. Sanchez CG, Ma CX, Crowder RJ, Guintoli T, Phommaly C, Gao F, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res 2011;13:R21.
40. Fox EM, Arteaga CL, Miller TW. Abrogating endocrine resistance by targeting ERa and PI3K in breast cancer. Front Oncol 2012;16:145.
41. Elkabets M, Vora S, Juric D, Morse N, Mino-Kenudson M, Muranen T, et al. mTORC1 Inhibition is required for sensitivity to PI3K p110a inhibitors in PIK3CA-mutant breast cancer. Sci Transl Med 2013;5: 196ra99.
42. Juric D,Gonzalez-Angulo AM, Burris HA,Mschuler M, Schellens J, Berlin J, et al. Preliminary safety, pharmacokinetics and anti-tumor activity of BYL719, an alpha-specific PI3K inhibitor in combination with fulvestrant: results from a phase I study. Cancer Res 2013;73(24 Suppl):Abstract P2-16-14.
43. Saura C, Sachdev J, Patel MR, Cervantes A, Juric D, Infante J, et al. Ph1b study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer. Cancer Res 2015;75(9 Suppl):Abstract PD5-2.
44. Vora SR, Juric D, Kim N, Mino-Kenudson M, Huynh T, Costa C, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell 2014;26:136-49
45. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009;11:R77.
46. Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, et al. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer 2011;18:333-45.
47. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of estrogen receptorpositive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomized phase 2 study. Lancet Oncol 2015;16:25-35.
48. Study of LEE011, BYL719 and Letrozole in Advanced ER+ Breast Cancer. ClinicalTrials. gov identifier: NCT01872260
49. Wallin JJ, Edgar KA, Guan J, BerryM, Prior WW, Lee L, et al. GDC-0980 is a novel class I PI3K/mTOR kinase inhibitor with robust activity in cancer models driven by the PI3K pathway. Mol Cancer Ther 2011;10: 2426-36.