Advertisement

Breast Cancer Research and Treatment

, Volume 169, Issue 3, pp 397–406 | Cite as

Targeting the PI3K/AKT/mTOR pathway in triple-negative breast cancer: a review

  • Ricardo L. B. CostaEmail author
  • Hyo Sook Han
  • William J. Gradishar
Review

Abstract

Purpose

Triple-negative breast cancer (TNBC) accounts for approximately 20% of breast cancer cases. Although there have been advances in the treatment of hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancers, targeted therapies for TNBC remain unavailable. In this narrative review, we summarize recent discoveries related to the underlying biology of the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway in TNBC, examine clinical progress to date, and suggest rational future approaches for investigational therapies in TNBC.

Results

As with other subtypes of breast cancer, aberrations in the PI3K/AKT/mTOR pathway are common in TNBC. Preclinical data support the notion that these aberrations predict TNBC inhibition by targeted agents. In a recently published phase 2 clinical trial, an AKT inhibitor (ipatasertib) improved outcomes in a subset of patients with metastatic TNBC when combined with paclitaxel in the first-line setting. In addition, new compounds with distinct specificity and potency targeting different PI3K/AKT/mTOR components and cognate molecules (e.g., mitogen-activated protein kinase) are being developed. These agents present a wide range of toxicity profiles and early efficacy signals, which must be considered prior to the advancement of new agents in later-phase clinical trials.

Conclusions

The development of drugs targeting the PI3K/AKT/mTOR pathway for the treatment of TNBC is an evolving field that should take into account the efficacies and toxicities of new agents in addition to their interactions with different cancer pathways.

Keywords

Triple-negative breast cancer Targeted therapy PI3K mTOR 

Notes

Acknowledgements

We thank Sonya Smyk (Moffitt Cancer Center) for editorial assistance. She received no compensation beyond her regular salary.

Funding

This research did not receive any specific grant funding from agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Disclosure

The authors declare no potential conflicts of interest.

References

  1. 1.
    Diaz LK, Cryns VL, Symmans WF, Sneige N (2007) Triple negative breast carcinoma and the basal phenotype: from expression profiling to clinical practice. Adv Anat Pathol 14(6):419–430.  https://doi.org/10.1097/PAP.0b013e3181594733 CrossRefPubMedGoogle Scholar
  2. 2.
    Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, Cristofanilli M, Hortobagyi GN, Pusztai L (2008) Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26(8):1275–1281.  https://doi.org/10.1200/JCO.2007.14.4147 CrossRefPubMedGoogle Scholar
  3. 3.
    Guarneri V, Broglio K, Kau SW, Cristofanilli M, Buzdar AU, Valero V, Buchholz T, Meric F, Middleton L, Hortobagyi GN, Gonzalez-Angulo AM (2006) Prognostic value of pathologic complete response after primary chemotherapy in relation to hormone receptor status and other factors. J Clin Oncol 24(7):1037–1044.  https://doi.org/10.1200/JCO.2005.02.6914 CrossRefPubMedGoogle Scholar
  4. 4.
    Rugo H, Thomas E, Blackwell K, Chung H, Lerzo G et al (2009) Ixabepilone plus capecitabine vs. capecitabine in patients with triple negative tumors: a pooled analysis of patients from two large phase III clinical studies. Can Res 69(2009):225Google Scholar
  5. 5.
    Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C (2004) Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol 22(19):3893–3901.  https://doi.org/10.1200/JCO.2004.08.157 CrossRefPubMedGoogle Scholar
  6. 6.
    Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Dieras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C, EMBRACE Investigators (2011) Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet 377(9769):914–923.  https://doi.org/10.1016/S0140-6736(11)60070-6 CrossRefPubMedGoogle Scholar
  7. 7.
    Cancer Genome Atlas N (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418):61–70.  https://doi.org/10.1038/nature11412 CrossRefGoogle Scholar
  8. 8.
    LoRusso PM (2016) Inhibition of the PI3K/AKT/mTOR pathway in solid tumors. J Clin Oncol.  https://doi.org/10.1200/JCO.2014.59.0018 CrossRefPubMedGoogle Scholar
  9. 9.
    Liu T, Yacoub R, Taliaferro-Smith LD, Sun SY, Graham TR, Dolan R, Lobo C, Tighiouart M, Yang L, Adams A, O’Regan RM (2011) Combinatorial effects of lapatinib and rapamycin in triple-negative breast cancer cells. Mol Cancer Ther 10(8):1460–1469.  https://doi.org/10.1158/1535-7163.MCT-10-0925 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Cossu-Rocca P, Orru S, Muroni MR, Sanges F, Sotgiu G, Ena S, Pira G, Murgia L, Manca A, Uras MG, Sarobba MG, Urru S, De Miglio MR (2015) Analysis of PIK3CA mutations and activation pathways in triple negative breast cancer. PLoS ONE 10(11):e0141763.  https://doi.org/10.1371/journal.pone.0141763 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ooms LM, Binge LC, Davies EM, Rahman P, Conway JR, Gurung R, Ferguson DT, Papa A, Fedele CG, Vieusseux JL, Chai RC, Koentgen F, Price JT, Tiganis T, Timpson P, McLean CA, Mitchell CA (2015) The inositol polyphosphate 5-phosphatase PIPP regulates AKT1-dependent breast cancer growth and metastasis. Cancer Cell 28(2):155–169.  https://doi.org/10.1016/j.ccell.2015.07.003 CrossRefPubMedGoogle Scholar
  12. 12.
    Liu H, Murphy CJ, Karreth FA, Emdal KB, White FM, Elemento O, Toker A, Wulf GM, Cantley LC (2017) Identifying and targeting sporadic oncogenic genetic aberrations in mouse models of triple negative breast cancer. Cancer Discov.  https://doi.org/10.1158/2159-8290.CD-17-0679 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529.  https://doi.org/10.1056/NEJMoa1109653 CrossRefPubMedGoogle Scholar
  14. 14.
    Kim SB, Dent R, Im SA, Espie M, Blau S, Tan AR, Isakoff SJ, Oliveira M, Saura C, Wongchenko MJ, Kapp AV, Chan WY, Singel SM, Maslyar DJ, Baselga J, LOTUS Investigators (2017) Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol.  https://doi.org/10.1016/S1470-2045(17)30450-3 CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, Fluge O, Pergamenschikov A, Williams C, Zhu SX, Lonning PE, Borresen-Dale AL, Brown PO, Botstein D (2000) Molecular portraits of human breast tumours. Nature 406(6797):747–752.  https://doi.org/10.1038/35021093 CrossRefPubMedGoogle Scholar
  16. 16.
    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Investig 121(7):2750–2767.  https://doi.org/10.1172/JCI45014 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Walsh S, Flanagan L, Quinn C, Evoy D, McDermott EW, Pierce A, Duffy MJ (2012) mTOR in breast cancer: differential expression in triple-negative and non-triple-negative tumors. Breast 21(2):178–182.  https://doi.org/10.1016/j.breast.2011.09.008 CrossRefPubMedGoogle Scholar
  18. 18.
    Kriegsmann M, Endris V, Wolf T, Pfarr N, Stenzinger A, Loibl S, Denkert C, Schneeweiss A, Budczies J, Sinn P, Weichert W (2014) Mutational profiles in triple-negative breast cancer defined by ultradeep multigene sequencing show high rates of PI3K pathway alterations and clinically relevant entity subgroup specific differences. Oncotarget 5(20):9952–9965.  https://doi.org/10.18632/oncotarget.2481 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Ueng SH, Chen SC, Chang YS, Hsueh S, Lin YC, Chien HP, Lo YF, Shen SC, Hsueh C (2012) Phosphorylated mTOR expression correlates with poor outcome in early-stage triple negative breast carcinomas. Int J Clin Exp Pathol 5(8):806–813PubMedPubMedCentralGoogle Scholar
  20. 20.
    Burger MT, Pecchi S, Wagman A, Ni ZJ, Knapp M, Hendrickson T, Atallah G, Pfister K, Zhang Y, Bartulis S, Frazier K, Ng S, Smith A, Verhagen J, Haznedar J, Huh K, Iwanowicz E, Xin X, Menezes D, Merritt H, Lee I, Wiesmann M, Kaufman S, Crawford K, Chin M, Bussiere D, Shoemaker K, Zaror I, Maira SM, Voliva CF (2011) Identification of NVP-BKM120 as a potent, selective, orally bioavailable class I PI3 kinase inhibitor for treating cancer. ACS Med Chem Lett 2(10):774–779.  https://doi.org/10.1021/ml200156t CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Baselga J, Im SA, Iwata H, Cortes J, De Laurentiis M, Jiang Z, Arteaga CL, Jonat W, Clemons M, Ito Y, Awada A, Chia S, Jagiello-Gruszfeld A, Pistilli B, Tseng LM, Hurvitz S, Masuda N, Takahashi M, Vuylsteke P, Hachemi S, Dharan B, Di Tomaso E, Urban P, Massacesi C, Campone M (2017) Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 18(7):904–916.  https://doi.org/10.1016/S1470-2045(17)30376-5 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sarker D, Ang JE, Baird R, Kristeleit R, Shah K, Moreno V, Clarke PA, Raynaud FI, Levy G, Ware JA, Mazina K, Lin R, Wu J, Fredrickson J, Spoerke JM, Lackner MR, Yan Y, Friedman LS, Kaye SB, Derynck MK, Workman P, de Bono JS (2015) First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors. Clin Cancer Res 21(1):77–86.  https://doi.org/10.1158/1078-0432.CCR-14-0947 CrossRefPubMedGoogle Scholar
  23. 23.
    Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, Chuckowree IS, Clarke PA, Depledge P, Eccles SA, Friedman LS, Hayes A, Hancox TC, Kugendradas A, Lensun L, Moore P, Olivero AG, Pang J, Patel S, Pergl-Wilson GH, Raynaud FI, Robson A, Saghir N, Salphati L, Sohal S, Ultsch MH, Valenti M, Wallweber HJ, Wan NC, Wiesmann C, Workman P, Zhyvoloup A, Zvelebil MJ, Shuttleworth SJ (2008) The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem 51(18):5522–5532.  https://doi.org/10.1021/jm800295d CrossRefPubMedGoogle Scholar
  24. 24.
    Krop IE, Mayer IA, Ganju V, Dickler M, Johnston S, Morales S, Yardley DA, Melichar B, Forero-Torres A, Lee SC, de Boer R, Petrakova K, Vallentin S, Perez EA, Piccart M, Ellis M, Winer E, Gendreau S, Derynck M, Lackner M, Levy G, Qiu J, He J, Schmid P (2016) Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol 17(6):811–821.  https://doi.org/10.1016/S1470-2045(16)00106-6 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Tzeng HE, Yang L, Chen K, Wang Y, Liu YR, Pan SL, Gaur S, Hu S, Yen Y (2015) The pan-PI3K inhibitor GDC-0941 activates canonical WNT signaling to confer resistance in TNBC cells: resistance reversal with WNT inhibitor. Oncotarget 6(13):11061–11073.  https://doi.org/10.18632/oncotarget.3568 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Tolaney S, Burris H, Gartner E, Mayer IA, Saura C, Maurer M, Ciruelos E, Garcia AA, Campana F, Wu B, Xu Y, Jiang J, Winer E, Krop I (2015) Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Res Treat 149(1):151–161.  https://doi.org/10.1007/s10549-014-3248-4 CrossRefPubMedGoogle Scholar
  27. 27.
    Peek GW, Tollefsbol TO (2016) Combinatorial PX-866 and raloxifene decrease Rb phosphorylation, cyclin E2 transcription, and proliferation of MCF-7 breast cancer cells. J Cell Biochem 117(7):1688–1696.  https://doi.org/10.1002/jcb.25462 CrossRefPubMedGoogle Scholar
  28. 28.
    Hoeflich KP, Guan J, Edgar KA, O’Brien C, Savage H, Wilson TR, Neve RM, Friedman LS, Wallin JJ (2016) The PI3K inhibitor taselisib overcomes letrozole resistance in a breast cancer model expressing aromatase. Genes Cancer 7(3–4):73–85.  https://doi.org/10.18632/genesandcancer.100 PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, Liu M, Kauffmann A, Guthy D, Erdmann D, De Pover A, Furet P, Gao H, Ferretti S, Wang Y, Trappe J, Brachmann SM, Maira SM, Wilson C, Boehm M, Garcia-Echeverria C, Chene P, Wiesmann M, Cozens R, Lehar J, Schlegel R, Caravatti G, Hofmann F, Sellers WR (2014) Characterization of the novel and specific PI3 Kalpha inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther 13(5):1117–1129.  https://doi.org/10.1158/1535-7163.MCT-13-0865 CrossRefPubMedGoogle Scholar
  30. 30.
    Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL (2017) A phase Ib study of alpelisib (BYL719), a PI3 Kalpha-specific inhibitor, with letrozole in ER+/HER2 metastatic breast cancer. Clin Cancer Res 23(1):26–34.  https://doi.org/10.1158/1078-0432.CCR-16-0134 CrossRefPubMedGoogle Scholar
  31. 31.
    Yuan Y, Mortimer J, Xing Q, Yan J, Wen W, Han E, Yim JH (2017) Synergistic suppression of triple negative breast cancer with the combination of PI3K inhibitor (alpelisib, BYL719) and CDK inhibitor (ribociclib, LEE011). In: Proceedings of the 2016 San Antonio breast cancer symposium, 2016 Dec 6–10, San Antonio, TX Philadelphia (PA)Google Scholar
  32. 32.
    Juric D, de Bono JS, LoRusso PM, Nemunaitis J, Heath EI, Kwak EL, Macarulla Mercade T, Geuna E, Jose de Miguel-Luken M, Patel C, Kuida K, Sankoh S, Westin EH, Zohren F, Shou Y, Tabernero J (2017) A first-in-human, phase I, dose-escalation study of TAK-117, a selective PI3 Kalpha isoform inhibitor, in patients with advanced solid malignancies. Clin Cancer Res 23(17):5015–5023.  https://doi.org/10.1158/1078-0432.CCR-16-2888 CrossRefPubMedGoogle Scholar
  33. 33.
    Lin J, Sampath D, Nannini MA, Lee BB, Degtyarev M, Oeh J, Savage H, Guan Z, Hong R, Kassees R, Lee LB, Risom T, Gross S, Liederer BM, Koeppen H, Skelton NJ, Wallin JJ, Belvin M, Punnoose E, Friedman LS, Lin K (2013) Targeting activated Akt with GDC-0068, a novel selective Akt inhibitor that is efficacious in multiple tumor models. Clin Cancer Res 19(7):1760–1772.  https://doi.org/10.1158/1078-0432.CCR-12-3072 CrossRefPubMedGoogle Scholar
  34. 34.
    Wisinski KB, Tevaarwerk AJ, Burkard ME, Rampurwala M, Eickhoff J, Bell MC, Kolesar JM, Flynn C, Liu G (2016) Phase I study of an AKT inhibitor (MK-2206) combined with lapatinib in adult solid tumors followed by dose expansion in advanced HER2+ breast cancer. Clin Cancer Res 22(11):2659–2667.  https://doi.org/10.1158/1078-0432.CCR-15-2365 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Schmid P, Wheatley D, Baird R, Chan S, Abraham J, Tutt A, Kristeleit H, Patel G, Bathakur U, Bishop J, Harper-Wynne C, Sims E, Copson E, Perren T, Stein R, Poole C, Cartwright H, Sarker S-J, Mousa K, Turner N (2016) A phase II, double blind, randomised, placebo-controlled study of the AKT inhibitor AZD5363 in combination with paclitaxel in triple-negative advanced or metastatic breast cancer (TNBC)(NCT02423603). In: Proceedings of the thirty-eighth annual CTRC-AACR San Antonio breast cancer symposium: 2015 Dec 8–12, San Antonio, TX Philadelphia (PA)Google Scholar
  36. 36.
    Leighl NB, Dent S, Clemons M, Vandenberg TA, Tozer R, Warr DG, Crump RM, Hedley D, Pond GR, Dancey JE, Moore MJ (2008) A phase 2 study of perifosine in advanced or metastatic breast cancer. Breast Cancer Res Treat 108(1):87–92.  https://doi.org/10.1007/s10549-007-9584-x CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang H, Cohen AL, Krishnakumar S, Wapnir IL, Veeriah S, Deng G, Coram MA, Piskun CM, Longacre TA, Herrler M, Frimannsson DO, Telli ML, Dirbas FM, Matin AC, Dairkee SH, Larijani B, Glinsky GV, Bild AH, Jeffrey SS (2014) Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to mTOR inhibition. Breast Cancer Res 16(2):R36.  https://doi.org/10.1186/bcr3640 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Basho RK, Gilcrease M, Murthy RK, Helgason T, Karp DD, Meric-Bernstam F, Hess KR, Herbrich SM, Valero V, Albarracin C, Litton JK, Chavez-MacGregor M, Ibrahim NK, Murray JL 3rd, Koenig KB, Hong D, Subbiah V, Kurzrock R, Janku F, Moulder SL (2017) Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer: evidence from a phase 1 trial of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab. JAMA Oncol 3(4):509–515.  https://doi.org/10.1001/jamaoncol.2016.5281 CrossRefPubMedGoogle Scholar
  39. 39.
    Hatem R, El Botty R, Chateau-Joubert S, Servely JL, Labiod D, de Plater L, Assayag F, Coussy F, Callens C, Vacher S, Reyal F, Cosulich S, Dieras V, Bieche I, Marangoni E (2016) Targeting mTOR pathway inhibits tumor growth in different molecular subtypes of triple-negative breast cancers. Oncotarget 7(30):48206–48219.  https://doi.org/10.18632/oncotarget.10195 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    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(3):673–682.  https://doi.org/10.1007/s10549-012-2298-8 CrossRefPubMedGoogle Scholar
  41. 41.
    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. Can Res 66(3):1500–1508.  https://doi.org/10.1158/0008-5472.CAN-05-2925 CrossRefGoogle Scholar
  42. 42.
    Xu S, Li S, Guo Z, Luo J, Ellis MJ, Ma CX (2013) Combined targeting of mTOR and AKT is an effective strategy for basal-like breast cancer in patient-derived xenograft models. Mol Cancer Ther 12(8):1665–1675.  https://doi.org/10.1158/1535-7163.MCT-13-0159 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Mallon R, Feldberg LR, Lucas J, Chaudhary I, Dehnhardt C, Santos ED, Chen Z, dos Santos O, Ayral-Kaloustian S, Venkatesan A, Hollander I (2011) Antitumor efficacy of PKI-587, a highly potent dual PI3K/mTOR kinase inhibitor. Clin Cancer Res 17(10):3193–3203.  https://doi.org/10.1158/1078-0432.CCR-10-1694 CrossRefPubMedGoogle Scholar
  44. 44.
    Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL (2012) Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci USA 109(8):2718–2723.  https://doi.org/10.1073/pnas.1018001108 CrossRefPubMedGoogle Scholar
  45. 45.
    Shapiro GI, Bell-McGuinn KM, Molina JR, Bendell J, Spicer J, Kwak EL, Pandya SS, Millham R, Borzillo G, Pierce KJ, Han L, Houk BE, Gallo JD, Alsina M, Brana I, Tabernero J (2015) First-in-human study of PF-05212384 (PKI-587), a small-molecule, intravenous, dual inhibitor of PI3K and mTOR in patients with advanced cancer. Clin Cancer Res 21(8):1888–1895.  https://doi.org/10.1158/1078-0432.CCR-14-1306 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Del Campo JM, Birrer M, Davis C, Fujiwara K, Gollerkeri A, Gore M, Houk B, Lau S, Poveda A, Gonzalez-Martin A, Muller C, Muro K, Pierce K, Suzuki M, Vermette J, Oza A (2016) A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer. Gynecol Oncol 142(1):62–69.  https://doi.org/10.1016/j.ygyno.2016.04.019 CrossRefPubMedGoogle Scholar
  47. 47.
    Sutherlin DP, Bao L, Berry M, Castanedo G, Chuckowree I, Dotson J, Folks A, Friedman L, Goldsmith R, Gunzner J, Heffron T, Lesnick J, Lewis C, Mathieu S, Murray J, Nonomiya J, Pang J, Pegg N, Prior WW, Rouge L, Salphati L, Sampath D, Tian Q, Tsui V, Wan NC, Wang S, Wei B, Wiesmann C, Wu P, Zhu BY, Olivero A (2011) Discovery of a potent, selective, and orally available class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) kinase inhibitor (GDC-0980) for the treatment of cancer. J Med Chem 54(21):7579–7587.  https://doi.org/10.1021/jm2009327 CrossRefPubMedGoogle Scholar
  48. 48.
    Wallin JJ, Edgar KA, Guan J, Berry M, Prior WW, Lee L, Lesnick JD, Lewis C, Nonomiya J, Pang J, 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(12):2426–2436.  https://doi.org/10.1158/1535-7163.MCT-11-0446 CrossRefPubMedGoogle Scholar
  49. 49.
    Knight SD, Adams ND, Burgess JL, Chaudhari AM, Darcy MG, Donatelli CA, Luengo JI, Newlander KA, Parrish CA, Ridgers LH, Sarpong MA, Schmidt SJ, Van Aller GS, Carson JD, Diamond MA, Elkins PA, Gardiner CM, Garver E, Gilbert SA, Gontarek RR, Jackson JR, Kershner KL, Luo L, Raha K, Sherk CS, Sung CM, Sutton D, Tummino PJ, Wegrzyn RJ, Auger KR, Dhanak D (2010) Discovery of GSK2126458, a highly potent inhibitor of PI3K and the mammalian target of rapamycin. ACS Med Chem Lett 1(1):39–43.  https://doi.org/10.1021/ml900028r CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Garcia-Echeverria C, Sellers WR (2008) Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene 27(41):5511–5526.  https://doi.org/10.1038/onc.2008.246 CrossRefPubMedGoogle Scholar
  51. 51.
    Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, Byrd JC, Tyner JW, Loriaux MM, Deininger M, Druker BJ, Puri KD, Ulrich RG, Giese NA (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(2):591–594.  https://doi.org/10.1182/blood-2010-03-275305 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Prenzel N, Zwick E, Leserer M, Ullrich A (2000) Tyrosine kinase signalling in breast cancer. Epidermal growth factor receptor: convergence point for signal integration and diversification. Breast Cancer Res 2(3):184–190CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Craig DW, O’Shaughnessy JA, Kiefer JA, Aldrich J, Sinari S, Moses TM, Wong S, Dinh J, Christoforides A, Blum JL, Aitelli CL, Osborne CR, Izatt T, Kurdoglu A, Baker A, Koeman J, Barbacioru C, Sakarya O, De La Vega FM, Siddiqui A, Hoang L, Billings PR, Salhia B, Tolcher AW, Trent JM, Mousses S, Von Hoff D, Carpten JD (2013) Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. Mol Cancer Ther 12(1):104–116.  https://doi.org/10.1158/1535-7163.MCT-12-0781 CrossRefPubMedGoogle Scholar
  54. 54.
    Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, Gendelman R, Bayani N, Wang NJ, Neve RM, Guan Y, Hu Z, Knight Z, Feiler HS, Gascard P, Parvin B, Spellman PT, Shokat KM, Wyrobek AJ, Bissell MJ, McCormick F, Kuo WL, Mills GB, Gray JW, Korn WM (2009) Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Can Res 69(2):565–572.  https://doi.org/10.1158/0008-5472.CAN-08-3389 CrossRefGoogle Scholar
  55. 55.
    Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Garcia-Echeverria C (2008) 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(7):1851–1863.  https://doi.org/10.1158/1535-7163.MCT-08-0017 CrossRefPubMedGoogle Scholar
  56. 56.
    Baldassarre G, Battista S, Belletti B, Thakur S, Pentimalli F, Trapasso F, Fedele M, Pierantoni G, Croce CM, Fusco A (2003) Negative regulation of BRCA1 gene expression by HMGA1 proteins accounts for the reduced BRCA1 protein levels in sporadic breast carcinoma. Mol Cell Biol 23(7):2225–2238CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Beger C, Pierce LN, Kruger M, Marcusson EG, Robbins JM, Welcsh P, Welch PJ, Welte K, King MC, Barber JR, Wong-Staal F (2001) Identification of Id4 as a regulator of BRCA1 expression by using a ribozyme-library-based inverse genomics approach. Proc Natl Acad Sci USA 98(1):130–135.  https://doi.org/10.1073/pnas.98.1.130 CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Esteller M, Silva JM, Dominguez G, Bonilla F, Matias-Guiu X, Lerma E, Bussaglia E, Prat J, Harkes IC, Repasky EA, Gabrielson E, Schutte M, Baylin SB, Herman JG (2000) Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J Natl Cancer Inst 92(7):564–569CrossRefPubMedGoogle Scholar
  59. 59.
    Ashworth A (2008) A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 26(22):3785–3790.  https://doi.org/10.1200/JCO.2008.16.0812 CrossRefPubMedGoogle Scholar
  60. 60.
    Kumar A, Fernandez-Capetillo O, Carrera AC (2010) Nuclear phosphoinositide 3-kinase beta controls double-strand break DNA repair. Proc Natl Acad Sci USA 107(16):7491–7496.  https://doi.org/10.1073/pnas.0914242107 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Ibrahim YH, Garcia-Garcia C, Serra V, He L, Torres-Lockhart K, Prat A, Anton P, Cozar P, Guzman M, Grueso J, Rodriguez O, Calvo MT, Aura C, Diez O, Rubio IT, Perez J, Rodon J, Cortes J, Ellisen LW, Scaltriti M, Baselga J (2012) PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition. Cancer Discov 2(11):1036–1047.  https://doi.org/10.1158/2159-8290.CD-11-0348 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    De P, Sun Y, Carlson JH, Friedman LS, Leyland-Jones BR, Dey N (2014) Doubling down on the PI3K-AKT-mTOR pathway enhances the antitumor efficacy of PARP inhibitor in triple negative breast cancer model beyond BRCA-ness. Neoplasia 16(1):43–72CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Nanda R, Chow LQ, Dees EC, Berger R, Gupta S, Geva R, Pusztai L, Pathiraja K, Aktan G, Cheng JD, Karantza V, Buisseret L (2016) Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 34(21):2460–2467.  https://doi.org/10.1200/JCO.2015.64.8931 CrossRefPubMedGoogle Scholar
  64. 64.
    Dirix LY TI, Nikolinakos P, Jerusalem G, Arkenau H-T, Hamilton EP, von Heydebreck A, Grote H-J, Chin K, Lippman ME (2015) [S1-04] Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase Ib JAVELIN solid tumor trial. In: San Antonio breast conference 2015Google Scholar
  65. 65.
    Champiat S, Ferte C, Lebel-Binay S, Eggermont A, Soria JC (2014) Exomics and immunogenics: bridging mutational load and immune checkpoints efficacy. Oncoimmunology 3(1):e27817.  https://doi.org/10.4161/onci.27817 CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su X, Wang Y, Gonzalez-Angulo AM, Akcakanat A, Chawla A, Curran M, Hwu P, Sharma P, Litton JK, Molldrem JJ, Alatrash G (2014) PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2(4):361–370.  https://doi.org/10.1158/2326-6066.cir-13-0127 CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Ndubaku CO, Heffron TP, Staben ST, Baumgardner M, Blaquiere N, Bradley E, Bull R, Do S, Dotson J, Dudley D, Edgar KA, Friedman LS, Goldsmith R, Heald RA, Kolesnikov A, Lee L, Lewis C, Nannini M, Nonomiya J, Pang J, Price S, Prior WW, Salphati L, Sideris S, Wallin JJ, Wang L, Wei B, Sampath D, Olivero AG (2013) Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a beta-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem 56(11):4597–4610.  https://doi.org/10.1021/jm4003632 CrossRefPubMedGoogle Scholar
  68. 68.
    Barlaam B, Cosulich S, Degorce S, Fitzek M, Green S, Hancox U, Lambert-van der Brempt C, Lohmann JJ, Maudet M, Morgentin R, Pasquet MJ, Peru A, Ple P, Saleh T, Vautier M, Walker M, Ward L, Warin N (2015) Discovery of (R)-8-(1-(3,5-difluorophenylamino)ethyl)-N, N-dimethyl-2-morpholino-4-oxo-4H-chrom ene-6-carboxamide (AZD8186): a potent and selective inhibitor of PI3 Kbeta and PI3 Kdelta for the treatment of PTEN-deficient cancers. J Med Chem 58(2):943–962.  https://doi.org/10.1021/jm501629p CrossRefPubMedGoogle Scholar
  69. 69.
    Sedrani R, Cottens S, Kallen J, Schuler W (1998) Chemical modification of rapamycin: the discovery of SDZ RAD. Transpl Proc 30(5):2192–2194CrossRefGoogle Scholar
  70. 70.
    Hirai H, Sootome H, Nakatsuru Y, Miyama K, Taguchi S, Tsujioka K, Ueno Y, Hatch H, Majumder PK, Pan BS, Kotani H (2010) MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol Cancer Ther 9(7):1956–1967.  https://doi.org/10.1158/1535-7163.MCT-09-1012 CrossRefPubMedGoogle Scholar
  71. 71.
    Addie M, Ballard P, Buttar D, Crafter C, Currie G, Davies BR, Debreczeni J, Dry H, Dudley P, Greenwood R, Johnson PD, Kettle JG, Lane C, Lamont G, Leach A, Luke RW, Morris J, Ogilvie D, Page K, Pass M, Pearson S, Ruston L (2013) Discovery of 4-amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J Med Chem 56(5):2059–2073.  https://doi.org/10.1021/jm301762v CrossRefPubMedGoogle Scholar
  72. 72.
    Pachl F, Plattner P, Ruprecht B, Medard G, Sewald N, Kuster B (2013) Characterization of a chemical affinity probe targeting Akt kinases. J Proteome Res 12(8):3792–3800.  https://doi.org/10.1021/pr400455j CrossRefPubMedGoogle Scholar
  73. 73.
    Shor B, Zhang WG, Toral-Barza L, Lucas J, Abraham RT, Gibbons JJ, Yu K (2008) A new pharmacologic action of CCI-779 involves FKBP12-independent inhibition of mTOR kinase activity and profound repression of global protein synthesis. Can Res 68(8):2934–2943.  https://doi.org/10.1158/0008-5472.CAN-07-6487 CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Breast Oncology, Moffitt McKinley Outpatient CenterH. Lee Moffitt Cancer Center and Research InstituteTampaUSA
  2. 2.Robert H. Lurie Comprehensive Cancer Center of Northwestern UniversityChicagoUSA

Personalised recommendations