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Expert Review of Obstetrics & Gynecology Volume 7, 2012 - Issue 5
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Review

PI3K–AKT–mTOR inhibitors for the systemic treatment of endometrial cancer

David N Church Oxford Cancer Centre, University of Oxford, Oxford, UK; Oxford Cancer Centre, University of Oxford, Oxford, UK
,
Romana Koppensteiner Laboratory of Gynecological Oncology, University Hospital of Zurich, Zurich, Switzerland; Laboratory of Gynecological Oncology, University Hospital of Zurich, Zurich, Switzerland
,
Timothy A Yap Royal Marsden Hospital, London, UK; Royal Marsden Hospital, London, UK
,
Daniel Fink Laboratory of Gynecological Oncology, University Hospital of Zurich, Zurich, Switzerland; Department of Gynecology, University Hospital of Zurich, Zurich, Switzerland; Laboratory of Gynecological Oncology, University Hospital of Zurich, Zurich, Switzerland; Department of Gynecology, University Hospital of Zurich, Zurich, Switzerland
&
Konstantin J Dedes Laboratory of Gynecological Oncology, University Hospital of Zurich, Zurich, Switzerland; Laboratory of Gynecological Oncology, University Hospital of Zurich, Zurich, Switzerland. [email protected]
Pages 421-430 | Published online: 10 Jan 2014

References

  • Sorosky JI. Endometrial cancer. Obstet. Gynecol. 111(2 Pt 1), 436–447 (2008).
  • Dedes KJ, Wetterskog D, Ashworth A, Kaye SB, Reis-Filho JS. Emerging therapeutic targets in endometrial cancer. Nat. Rev. Clin. Oncol. 8(5), 261–271 (2011).
  • Dellinger TH, Monk BJ. Systemic therapy for recurrent endometrial cancer: a review of North American trials. Expert Rev. Anticancer Ther. 9(7), 905–916 (2009).
  • Salvesen HB, Carter SL, Mannelqvist M et al. Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc. Natl Acad. Sci. USA 106(12), 4834–4839 (2009).
  • Vanhaesebroeck B, Welham MJ, Kotani K et al. P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc. Natl Acad. Sci. USA 94(9), 4330–4335 (1997).
  • Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB. Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat. Rev. Drug Discov. 4(12), 988–1004 (2005).
  • Bader AG, Kang S, Zhao L, Vogt PK. Oncogenic PI3K deregulates transcription and translation. Nat. Rev. Cancer 5(12), 921–929 (2005).
  • Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat. Rev. Genet. 7(8), 606–619 (2006).
  • Cantley LC. The phosphoinositide 3-kinase pathway. Science 296(5573), 1655–1657 (2002).
  • Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 17, 615–675 (2001).
  • Yuan TL, Cantley LC. PI3K pathway alterations in cancer: variations on a theme. Oncogene 27(41), 5497–5510 (2008).
  • Kang S, Denley A, Vanhaesebroeck B, Vogt PK. Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 103(5), 1289–1294 (2006).
  • 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(1), 83–90 (1991).
  • Zhao L, Vogt PK. Class I PI3K in oncogenic cellular transformation. Oncogene 27(41), 5486–5496 (2008).
  • Stephens L, Smrcka A, Cooke FT, Jackson TR, Sternweis PC, Hawkins PT. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits. Cell 77(1), 83–93 (1994).
  • Shaw RJ, Cantley LC. Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441(7092), 424–430 (2006).
  • Markman B, Atzori F, Pérez-García J, Tabernero J, Baselga J. Status of PI3K inhibition and biomarker development in cancer therapeutics. Ann. Oncol. 21(4), 683–691 (2010).
  • Hiles ID, Otsu M, Volinia S et al. Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell 70(3), 419–429 (1992).
  • Matheny RW Jr, Adamo ML. PI3K p110 alpha and p110 beta have differential effects on Akt activation and protection against oxidative stress-induced apoptosis in myoblasts. Cell Death Differ. 17(4), 677–688 (2010).
  • Roche S, Downward J, Raynal P, Courtneidge SA. A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction. Mol. Cell. Biol. 18(12), 7119–7129 (1998).
  • Patrucco E, Notte A, Barberis L et al. PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118(3), 375–387 (2004).
  • Sasaki T, Irie-Sasaki J, Jones RG et al. Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 287(5455), 1040–1046 (2000).
  • Backer JM. The regulation and function of Class III PI3Ks: novel roles for Vps34. Biochem. J. 410(1), 1–17 (2008).
  • Jaber N, Dou Z, Chen JS et al. Class III PI3K Vps34 plays an essential role in autophagy and in heart and liver function. Proc. Natl Acad. Sci. USA 109(6), 2003–2008 (2012).
  • 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(13), 9478–9483 (1993).
  • Songyang Z, Shoelson SE, Chaudhuri M et al. SH2 domains recognize specific phosphopeptide sequences. Cell 72(5), 767–778 (1993).
  • 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(6), 931–943 (2000).
  • Sansal I, Sellers WR. The biology and clinical relevance of the PTEN tumor suppressor pathway. J. Clin. Oncol. 22(14), 2954–2963 (2004).
  • Cully M, You H, Levine AJ, Mak TW. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat. Rev. Cancer 6(3), 184–192 (2006).
  • Milburn CC, Deak M, Kelly SM, Price NC, Alessi DR, Van Aalten DM. Binding of phosphatidylinositol 3,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem. J. 375(Pt 3), 531–538 (2003).
  • Huang BX, Akbar M, Kevala K, Kim HY. Phosphatidylserine is a critical modulator for Akt activation. J. Cell Biol. 192(6), 979–992 (2011).
  • Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer 2(7), 489–501 (2002).
  • Stephens L, Anderson K, Stokoe D et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 279(5351), 710–714 (1998).
  • Wendel HG, De Stanchina E, Fridman JS et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 428(6980), 332–337 (2004).
  • Luo J, Manning BD, Cantley LC. Targeting the PI3K–Akt pathway in human cancer: rationale and promise. Cancer Cell 4(4), 257–262 (2003).
  • Zoncu R, Efeyan A, Sabatini DM. mTOR: from growth signal integration to cancer, diabetes and ageing. Nat. Rev. Mol. Cell Biol. 12(1), 21–35 (2011).
  • Kim DH, Sarbassov DD, Ali SM et al. mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2), 163–175 (2002).
  • Sarbassov DD, Ali SM, Kim DH et al. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr. Biol. 14(14), 1296–1302 (2004).
  • Dowling RJ, Topisirovic I, Fonseca BD, Sonenberg N. Dissecting the role of mTOR: lessons from mTOR inhibitors. Biochim. Biophys. Acta 1804(3), 433–439 (2010).
  • Sarbassov DD, Ali SM, Sengupta S et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol. Cell 22(2), 159–168 (2006).
  • Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor–mTOR complex. Science 307(5712), 1098–1101 (2005).
  • Mirza AM, Kohn AD, Roth RA, McMahon M. Oncogenic transformation of cells by a conditionally active form of the protein kinase Akt/PKB. Cell Growth Differ. 11(6), 279–292 (2000).
  • Di Cristofano A, Pesce B, Cordon-Cardo C, Pandolfi PP. Pten is essential for embryonic development and tumour suppression. Nat. Genet. 19(4), 348–355 (1998).
  • Podsypanina K, Ellenson LH, Nemes A et al. Mutation of PTEN/Mmac1 in mice causes neoplasia in multiple organ systems. Proc. Natl Acad. Sci. USA. 96(4), 1563–1568 (1999).
  • Daikoku T, Hirota Y, Tranguch S et al. Conditional loss of uterine PTEN unfailingly and rapidly induces endometrial cancer in mice. Cancer Res. 68(14), 5619–5627 (2008).
  • Wee S, Wiederschain D, Maira SM et al. PTEN-deficient cancers depend on PIK3CB. Proc. Natl Acad. Sci. USA 105(35), 13057–13062 (2008).
  • Oda K, Stokoe D, Taketani Y, McCormick F. High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res. 65(23), 10669–10673 (2005).
  • 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(1), 145–148 (2009).
  • Murayama-Hosokawa S, Oda K, Nakagawa S et al. Genome-wide single-nucleotide polymorphism arrays in endometrial carcinomas associate extensive chromosomal instability with poor prognosis and unveil frequent chromosomal imbalances involved in the PI3-kinase pathway. Oncogene 29(13), 1897–1908 (2010).
  • Dutt A, Salvesen HB, Greulich H, Sellers WR, Beroukhim R, Meyerson M. Somatic mutations are present in all members of the AKT family in endometrial carcinoma. Br. J. Cancer 101(7), 1218–1219; author reply 1220 (2009).
  • Cheung LW, Hennessy BT, Li J et al. High frequency of PIK3R1 and PIK3R2 mutations in endometrial cancer elucidates a novel mechanism for regulation of PTEN protein stability. Cancer Discov. 1(2), 170–185 (2011).
  • Oda K, Okada J, Timmerman L et al. PIK3CA cooperates with other phosphatidylinositol 3´-kinase pathway mutations to effect oncogenic transformation. Cancer Res. 68(19), 8127–8136 (2008).
  • Weigelt B, Warne PH, Downward J. PIK3CA mutation, but not PTEN loss of function, determines the sensitivity of breast cancer cells to mTOR inhibitory drugs. Oncogene 30(29), 3222–3233 (2011).
  • Shoji K, Oda K, Kashiyama T et al. Genotype-dependent efficacy of a dual PI3K/mTOR inhibitor, NVP-BEZ235, and an mTOR inhibitor, RAD001, in endometrial carcinomas. PLoS ONE 7(5), e37431 (2012).
  • Prahallad A, Sun C, Huang S et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483(7387), 100–103 (2012).
  • Bain J, McLauchlan H, Elliott M, Cohen P. The specificities of protein kinase inhibitors: an update. Biochem. J. 371(Pt 1), 199–204 (2003).
  • 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(4), 841–850 (2008).
  • 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(1), 97–110 (2008).
  • 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(9), 2505–2514 (2007).
  • 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 non-small cell lung cancer xenografts. Mol. Cancer Ther. 4(9), 1349–1357 (2005).
  • Hirai H, Sootome H, Nakatsuru Y et al. 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 (2010).
  • 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(8), e3065 (2008).
  • Guertin DA, Sabatini DM. The pharmacology of mTOR inhibition. Sci. Signal. 2(67), pe24 (2009).
  • Feldman ME, Apsel B, Uotila A et al. Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7(2), e38 (2009).
  • 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(12), 8023–8032 (2009).
  • 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(15), 6232–6240 (2009).
  • 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(7), 1851–1863 (2008).
  • Wallin JJ, Edgar KA, Guan J 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. 10(12), 2426–2436 (2011).
  • 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(19), 8022–8030 (2008).
  • 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(1), 143–150 (2009).
  • Tanaka H, Yoshida M, Tanimura H et al. The selective class I PI3K inhibitor CH5132799 targets human cancers harboring oncogenic PIK3CA mutations. Clin. Cancer Res. 17(10), 3272–3281 (2011).
  • 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(12), 1351–1356 (2008).
  • Neshat MS, Mellinghoff IK, Tran C et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98(18), 10314–10319 (2001).
  • Noh WC, Mondesire WH, Peng J et al. Determinants of rapamycin sensitivity in breast cancer cells. Clin. Cancer Res. 10(3), 1013–1023 (2004).
  • Squillace RM, Miller D, Cookson M et al. Antitumor activity of ridaforolimus and potential cell-cycle determinants of sensitivity in sarcoma and endometrial cancer models. Mol. Cancer Ther. 10(10), 1959–1968 (2011).
  • Yang L, Clarke MJ, Carlson BL et al. PTEN loss does not predict for response to RAD001 (Everolimus) in a glioblastoma orthotopic xenograft test panel. Clin. Cancer Res. 14(12), 3993–4001 (2008).
  • Chen ML, Xu PZ, Peng XD et al. The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/- mice. Genes Dev. 20(12), 1569–1574 (2006).
  • Bayascas JR, Leslie NR, Parsons R, Fleming S, Alessi DR. Hypomorphic mutation of PDK1 suppresses tumorigenesis in PTEN(+/-) mice. Curr. Biol. 15(20), 1839–1846 (2005).
  • Church DN, Phillips BR, Stuckey DJ et al. Igf2 ligand dependency of Pten(+/-) developmental and tumour phenotypes in the mouse. Oncogene 31(31), 3635–3646 (2012).
  • Xu PZ, Chen ML, Jeon SM, Peng XD, Hay N. The effect Akt2 deletion on tumor development in Pten(+/-) mice. Oncogene 31(4), 518–526 (2012).
  • Cully M, Elia A, Ong SH et al. grb2 heterozygosity rescues embryonic lethality but not tumorigenesis in PTEN+/- mice. Proc. Natl Acad. Sci. USA 101(43), 15358–15363 (2004).
  • Berenjeno IM, Guillermet-Guibert J, Pearce W, Gray A, Fleming S, Vanhaesebroeck B. Both p110α and p110b isoforms of PI3K can modulate the impact of loss-of-function of the PTEN tumour suppressor. Biochem. J. 442(1), 151–159 (2012).
  • Jia S, Liu Z, Zhang S et al. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454(7205), 776–779 (2008).
  • Ellwood-Yen K, Keilhack H, Kunii K et al. PDK1 attenuation fails to prevent tumor formation in PTEN-deficient transgenic mouse models. Cancer Res. 71(8), 3052–3065 (2011).
  • Altomare DA, Zhang L, Deng J et al. GSK690693 delays tumor onset and progression in genetically defined mouse models expressing activated Akt. Clin. Cancer Res. 16(2), 486–496 (2010).
  • O’Reilly KE, Rojo F, She QB et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66(3), 1500–1508 (2006).
  • Chandarlapaty S, Sawai A, Scaltriti M et al. AKT inhibition relieves feedback suppression of receptor tyrosine kinase expression and activity. Cancer Cell 19(1), 58–71 (2011).
  • Sos ML, Fischer S, Ullrich R et al. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc. Natl Acad. Sci. USA 106(43), 18351–18356 (2009).
  • Stallone G, Schena A, Infante B et al. Sirolimus for Kaposi’s sarcoma in renal-transplant recipients. N. Engl. J. Med. 352(13), 1317–1323 (2005).
  • Oza AM, Elit L, Tsao MS et al. Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group. J. Clin. Oncol. 29(24), 3278–3285 (2011).
  • Alvarez EB, Walker J, Rotmensch J et al. Phase II trial of combination bevacizumab and temsirolimus in the treatment of recurrent or persistent endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol. Oncol. 125, S40 (2012).
  • Slomovitz BM, Lu KH, Johnston T et al. A Phase 2 study of the oral mammalian target of rapamycin inhibitor, everolimus, in patients with recurrent endometrial carcinoma. Cancer 116(23), 5415–5419 (2010).
  • Colombo NM, Schwartz P, Kostka J et al. A Phase II trial of the mTOR inhibitor AP23573 as a single agent in advanced endometrial cancer J. Clin. Oncol. 25, 18S Abstract 5518 (2007).
  • Mackay HJW, Tsao MS, Tsao MS et al. Phase II study of oral ridaforolimus in patients with metastatic and/or locally advanced recurrent endometrial cancer: NCIC CTG IND 192. J. Clin. Oncol. 29(Suppl.; abstr 5013) (2011).
  • Baselga J, Campone M, Piccart M et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N. Engl. J. Med. 366(6), 520–529 (2012).
  • Slomovitz BMB, Johnston T, Mura D et al. A Phase II study of everolimus and letrozole in patients with recurrent endometrial carcinoma. J. Clin. Oncol. 29(Suppl.; abstr 5012) (2011).
  • Janku F, Wheler JJ, Westin SN et al. PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. J. Clin. Oncol. 30(8), 777–782 (2012).
  • Yap TA, Garrett MD, Walton MI, Raynaud F, de Bono JS, Workman P. Targeting the PI3K–AKT–mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol. 8(4), 393–412 (2008).
  • Luo Y, Shoemaker AR, Liu X et al. Potent and selective inhibitors of Akt kinases slow the progress of tumors in vivo. Mol. Cancer Ther. 4(6), 977–986 (2005).
  • Grimshaw KM, Hunter LJ, Yap TA et al. AT7867 is a potent and oral inhibitor of AKT and p70 S6 kinase that induces pharmacodynamic changes and inhibits human tumor xenograft growth. Mol. Cancer Ther. 9(5), 1100–1110 (2010).
  • Lyons TR, Thorburn J, Ryan PW, Thorburn A, Anderson SM, Kassenbrock CK. Regulation of the pro-apoptotic scaffolding protein POSH by Akt. J. Biol. Chem. 282(30), 21987–21997 (2007).
  • Yap TA, Walton MI, Hunter LJ et al. Preclinical pharmacology, antitumor activity, and development of pharmacodynamic markers for the novel, potent AKT inhibitor CCT128930. Mol. Cancer Ther. 10(2), 360–371 (2011).
  • Bilodeau MT, Balitza AE, Hoffman JM et al. Allosteric inhibitors of Akt1 and Akt2: a naphthyridinone with efficacy in an A2780 tumor xenograft model. Bioorg. Med. Chem. Lett. 18(11), 3178–3182 (2008).
  • Yap TA, Patnaik A, Fearen I et al. First-in-class Phase I trial of a selective Akt inhibitor, MK2206, evaluating alternate day and once weekly doses in advanced cancer patients with evidence of target modulation and antitumor activity. J. Clin. Oncol. 28, 15s (Suppl.; abstr 3009) (2010).
  • Raynaud FI, Eccles SA, Patel S et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941. Mol. Cancer Ther. 8(7), 1725–1738 (2009).
  • Workman P, Clarke PA, Raynaud FI, van Montfort RL. Drugging the PI3 kinome: from chemical tools to drugs in the clinic. Cancer Res. 70(6), 2146–2157 (2010).
  • Lannutti BJ, Meadows SA, Herman SE et al. 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 (2011).

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