The PI3K/mTOR dual inhibitor P7170 demonstrates potent activity against endocrine-sensitive and endocrine-resistant ER+ breast cancer

Breast Cancer Research and Treatment

Volumn 149, Issue 1, 2015, Pages 69-79

  Bean, Jennifer R ^a   Hosford, Sarah R ^a   Symonds, Lynn K ^a   Owens, Philip ^b   Dillon, Lloye M ^a   Yang, Wei ^a   Shee, Kevin ^a   Schwartz, Gary N ^a   Marotti, Jonathan D ^a   Muller, Kristen E ^a   Rosenkranz, Kari M ^a   Barth, Richard J ^a   Chen, Vivian S ^a   Agarwal, Veena R ^c   Miller, Todd W ^a,d  

^a DARTMOUTH MEDICAL SCHOOL   (United States)

^b VANDERBILT UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Piramal Enterprises Limited   (India)

^d DARTMOUTH HITCHCOCK MEDICAL CENTER   (United States)

Author keywords

Anti estrogen; Breast; Estrogen; mTOR; PI3K

Indexed keywords

ANTINEOPLASTIC AGENT; EPIDERMAL GROWTH FACTOR RECEPTOR 2; FULVESTRANT; MAMMALIAN TARGET OF RAPAMYCIN; P 7170; PHOSPHATIDYLINOSITOL 3 KINASE; UNCLASSIFIED DRUG; ESTRADIOL; ESTROGEN RECEPTOR; IMIDAZOLE DERIVATIVE; MTOR PROTEIN, HUMAN; P7170 COMPOUND; PROTEIN KINASE INHIBITOR; QUINOLINE DERIVATIVE; TARGET OF RAPAMYCIN KINASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; APOPTOSIS; ARTICLE; BREAST CANCER CELL LINE; CANCER INHIBITION; CASE REPORT; CELL PROLIFERATION; CELL VIABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENCY; DRUG SCREENING; ENZYME INHIBITION; ESTROGEN RECEPTOR POSITIVE BREAST CANCER; EX VIVO STUDY; FEMALE; HUMAN; HUMAN TISSUE; MOUSE; NONHUMAN; PRIORITY JOURNAL; TUMOR VOLUME; ANALOGS AND DERIVATIVES; ANIMAL; ANTAGONISTS AND INHIBITORS; BREAST NEOPLASMS; DRUG EFFECTS; DRUG RESISTANCE; ENDOCRINE GLAND NEOPLASMS; GENE EXPRESSION REGULATION; GENETICS; MCF 7 CELL LINE; PATHOLOGY; SIGNAL TRANSDUCTION;

ANIMALS; APOPTOSIS; BREAST NEOPLASMS; CELL PROLIFERATION; DRUG RESISTANCE, NEOPLASM; ENDOCRINE GLAND NEOPLASMS; ESTRADIOL; FEMALE; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; IMIDAZOLES; MCF-7 CELLS; MICE; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; QUINOLINES; RECEPTORS, ESTROGEN; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84925517350     PISSN: 01676806     EISSN: 15737217     Source Type: Journal    
DOI: 10.1007/s10549-014-3201-6     Document Type: Article

References (43)

1. Ferlay JS, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Intern J Cancer 2010:2893–2917
2. Metzger-Filho O, Sun Z, Viale G, Price KN, Crivellari D, Snyder RD, Gelber RD, Castiglione-Gertsch M, Coates AS, Goldhirsch A, Cardoso F (2013) Patterns of Recurrence and outcome according to breast cancer subtypes in lymph node-negative disease: results from international breast cancer study group trials VIII and IX. J Clin Oncol 31:3083–3090
3. O’Brien KM, Cole SR, Tse CK, Perou CM, Carey LA, Foulkes WD, Dressler LG, Geradts J, Millikan RC (2010) Intrinsic breast tumor subtypes, race, and long-term survival in the Carolina Breast Cancer Study. Clin Cancer Res 16:6100–6110
4. Bentzon N, During M, Rasmussen BB, Mouridsen H, Kroman N (2008) Prognostic effect of estrogen receptor status across age in primary breast cancer. Int J Cancer 122:1089–1094
5. Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF, investigators AL (2010) Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 11:1135–1141
6. Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490:61–70
7. Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, Antipin Y, Reva B, Goldberg AP, Sander C, Schultz N (2012) The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov 2:401–404
8. Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H, Higham C, Garcia-Echeverria C, Shyr Y, Arteaga CL (2010) Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest 120:2406–2413
9. Campbell RA, Bhat-Nakshatri P, Patel NM, Constantinidou D, Ali S, Nakshatri H (2001) Phosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 276:9817–9824
10. Miller TW, Perez-Torres M, Narasanna A, Guix M, Stal O, Perez-Tenorio G, Gonzalez-Angulo AM, Hennessy BT, Mills GB, Kennedy JP, Lindsley CW, Arteaga CL (2009) Loss of phosphatase and tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-i receptor signaling to promote antiestrogen resistance in breast cancer. Cancer Res 69:4192–4201
11. Shou J, Massarweh S, Osborne CK, Wakeling AE, Ali S, Weiss H, Schiff R (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu cross-talk in ER/HER2− positive breast cancer. J Natl Cancer Inst 96:926–935
12. Sabnis G, Goloubeva O, Jelovac D, Schayowitz A, Brodie A (2007) Inhibition of the phosphatidylinositol 3-kinase/Akt pathway improves response of long-term estrogen-deprived breast cancer xenografts to antiestrogens. Clin Cancer Res 13:2751–2757
13. Crowder RJ, Phommaly C, Tao Y, Hoog J, Luo J, Perou CM, Parker JS, Miller MA, Huntsman DG, Lin L, Snider J, Davies SR, Olson JA Jr, Watson MA, Saporita A, Weber JD, Ellis MJ (2009) PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res 69:3955–3962
14. Miller TW, Balko JM, Fox EM, Ghazoui Z, Dunbier A, Anderson H, Dowsett M, Jiang A, Smith RA, Maira SM, Manning HC, Gonzalez-Angulo AM, Mills GB, Higham C, Chanthaphaychith S, Kuba MG, Miller WR, Shyr Y, Arteaga CL (2011) ERalpha-dependent E2F transcription can mediate resistance to estrogen deprivation in human breast cancer. Cancer Discov 1:338–351
15. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chene P, Shoemaker K, De Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, Garcia-Echeverria C, Sellers WR, Voliva CF (2012) Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther 11:317–328
16. Agarwal VR, Joshi A, Venkataraman M, Desai N, Bhatia D, Chaudhari S, Bose J, Kolla LS, Deore V, Yewalkar N, Kumar S, Sharma R, Damre A, More A, Gill P, Sharma S (2012) P7170: a potent and oral phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) inhibitor with anti-tumor and anti-angiogenic activity. Cancer Res 72:Abstract 3742
17. Agarwal VR, Joshi A, Venkataraman M, Bhatia D, Bose J, Kolla LS, Gill P, Sharma S (2012) P7170, a novel inhibitor of phosphoinositide 3-kinase (PI3K)-mammalian target of Rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) as a new therapeutic option for Kras mutated non small cell lung cancer (NSCLC) Cancer Res 72:Abstract 3759
18. Vichai V, Kirtikara K (2006) Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat Protoc 1:1112–1116
19. Miller TW, Forbes JT, Shah C, Wyatt SK, Manning HC, Olivares MG, Sanchez V, Dugger TC, de Matos Granja N, Narasanna A, Cook RS, Kennedy JP, Lindsley CW, Arteaga CL (2009) Inhibition of mammalian target of rapamycin is required for optimal antitumor effect of HER2 inhibitors against HER2-overexpressing cancer cells. Clin Cancer Res 15:7266–7276
20. 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
21. Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118:3065–3074
22. Hanada M, Feng J, Hemmings BA (2004) Structure, regulation and function of PKB/AKT–a major therapeutic target. Biochim Biophys Acta 1697:3–16
23. Scheid MP, Marignani PA, Woodgett JR (2002) Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B. Mol Cell Biol 22:6247–6260
24. Drabsch Y, ten Dijke P (2011) TGF-beta signaling in breast cancer cell invasion and bone metastasis. J Mammary Gland Biol Neoplasia 16:97–108
25. Destefano MA, Jacinto E (2013) Regulation of insulin receptor substrate-1 by mTORC2 (mammalian target of rapamycin complex 2). Biochem Soc Trans 41:896–901
26. Brachmann SM, Hofmann I, Schnell C, Fritsch C, Wee S, Lane H, Wang S, Garcia-Echeverria C, Maira SM (2009) Specific apoptosis induction by the dual PI3K/mTor inhibitor NVP-BEZ235 in HER2 amplified and PIK3CA mutant breast cancer cells. Proc Natl Acad Sci USA
27. Faber AC, Corcoran RB, Ebi H, Sequist LV, Waltman BA, Chung E, Incio J, Digumarthy SR, Pollack SF, Song Y, Muzikansky A, Lifshits E, Roberge S, Coffman EJ, Benes CH, Gomez HL, Baselga J, Arteaga CL, Rivera MN, Dias-Santagata D, Jain RK, Engelman JA (2011) BIM expression in treatment-naive cancers predicts responsiveness to kinase inhibitors. Cancer Discov 1:352–365
28. Bamford S, Dawson E, Forbes S, Clements J, Pettett R, Dogan A, Flanagan A, Teague J, Futreal PA, Stratton MR, Wooster R (2004) The COSMIC (Catalogue of Somatic Mutations in Cancer) database and website. Br J Cancer 91:355–358
29. Schnell CR, Stauffer F, Allegrini PR, O’Reilly T, McSheehy PM, Dartois C, Stumm M, Cozens R, Littlewood-Evans A, Garcia-Echeverria C, Maira SM (2008) Effects of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235 on the tumor vasculature: implications for clinical imaging. Cancer Res 68:6598–6607
30. Mabuchi S, Altomare DA, Connolly DC, Klein-Szanto A, Litwin S, Hoelzle MK, Hensley HH, Hamilton TC, Testa JR (2007) RAD001 (everolimus) delays tumor onset and progression in a transgenic mouse model of ovarian cancer. Cancer Res 67:2408–2413
31. Miller TW, Rexer BN, Garrett JT, Arteaga CL (2011) Mutations in the phosphatidylinositol 3-kinase pathway: role in tumor progression and therapeutic implications in breast cancer. Breast Cancer Res 13:224
32. Kang SA, Pacold ME, Cervantes CL, Lim D, Lou HJ, Ottina K, Gray NS, Turk BE, Yaffe MB, Sabatini DM (2013) mTORC1 phosphorylation sites encode their sensitivity to starvation and rapamycin. Science 341:364
33. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D, Shokat KM (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7:371–383
34. Choo AY, Yoon SO, Kim SG, Roux PP, Blenis J (2008) Rapamycin differentially inhibits S6Ks and 4E-BP1 to mediate cell-type-specific repression of mRNA translation. P Natl Acad Sci USA 105:17414–17419
35. Hassan B, Akcakanat A, Sangai T, Evans KW, Adkins F, Eterovic AK, Zhao H, Chen K, Chen H, Do KA, Xie SM, Holder AM, Naing A, Mills GB, Meric-Bernstam F (2014) Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors. Oncotarget 5:8544–8557
36. Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, Ruan DT, Hanna GJ, Haddad RI, Getz G, Kwiatkowski DJ, Carter SL, Sabatini DM, Janne PA, Garraway LA, Lorch JH (2014) Response and acquired resistance to everolimus in anaplastic thyroid cancer. N Engl J Med 371:1426–1433
37. Gokmen-Polar Y, Liu Y, Toroni RA, Sanders KL, Mehta R, Badve S, Rommel C, Sledge GW Jr (2012) Investigational drug MLN0128, a novel TORC1/2 inhibitor, demonstrates potent oral antitumor activity in human breast cancer xenograft models. Breast Cancer Res Treat 136:673–682
38. Wallin JJ, Edgar KA, Guan JE, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang JD, Salphati L, Olivero AG, Sutherlin DP, O’Brien C, Spoerke JM, Patel S, Lensun L, Kassees R, Ross L, Lackner MR, Sampath D, Belvin M, Friedman LS (2011) 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 10:2426–2436
39. Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J (2008) NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res 68:8022–8030
40. Spoerke JM, O’Brien C, Huw L, Koeppen H, Fridlyand J, Brachmann RK, Haverty PM, Pandita A, Mohan S, Sampath D, Friedman LS, Ross L, Hampton GM, Amler LC, Shames DS, Lackner MR (2012) Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models. Clin Cancer Res 18:6771–6783
41. Janku F, Hong DS, Fu S, Piha-Paul SA, Naing A, Falchook GS, Tsimberidou AM, Stepanek VM, Moulder SL, Lee JJ, Luthra R, Zinner RG, Broaddus RR, Wheler JJ, Kurzrock R (2014) Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors. Cell reports 6:377–387
42. Bendell JC, Rodon J, Burris HA, de Jonge M, Verweij J, Birle D, Demanse D, De Buck SS, Ru QC, Peters M, Goldbrunner M, Baselga J (2012) Phase I, dose-escalation study of BKM120, an oral pan-Class I PI3K inhibitor, in patients with advanced solid tumors. J Clin Oncol 30:282–290
43. Mayer IA, Abramson VG, Isakoff SJ, Forero A, Balko JM, Kuba MG, Sanders ME, Yap JT, Van den Abbeele AD, Li Y, Cantley LC, Winer E, Arteaga CL (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 32:1202–1209