PI3K抑制剂与其他药物联用克服耐药性的研究进展

贾成舒; 王均伟; 李慧; 朱启华; 葛亦然; 徐云根

doi:10.11665/j.issn.1000-5048.20170503

PI3K抑制剂与其他药物联用克服耐药性的研究进展

中国药科大学药物化学系

基金项目: 国家自然科学基金资助项目(No.81502928)；江苏高等学校优秀科技创新团队资助项目(2015)

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出版历程
- 刊出日期: 2017-10-24

Advances of phosphoinositide-3 kinase inhibitors in combination with other drugs to overcome drug resistance

摘要

摘要: 磷脂酰肌醇3-激酶(PI3K)是细胞内重要的信号传导分子，在细胞存活、增殖和分化过程中发挥着关键的调节作用。PI3K抑制剂在肿瘤治疗方面的研究取得了重大的进展，然而，PI3K抑制剂耐药性的出现，影响了其在临床上的长期疗效。为了克服PI3K抑制剂的耐药性，临床上发展了多种合理的药物组合方法来提高疗效，克服耐药性。本文就PI3K抑制剂与其他药物联用以克服耐药性的研究进展进行了综述。
- 磷脂酰肌醇3-激酶 /
- PI3K抑制剂 /
- 抗肿瘤 /
- 药物联用 /
- 耐药性
Abstract: Phosphoinositide 3-kindase, an important signal transduction molecule in cells, plays a key role in the process of cell survival, proliferation and differentiation. Significant progress has been made in the treatment of cancer with PI3K inhibitors, yet the drug resistance of PI3K inhibitors affects their long-term efficacy in clinical treatment. In order to overcome the drug resistance, a variety of rational combined therapies have been developed. In this paper, the research progress of phosphoinositide-3 kinase inhibitors in combination with other drugs to overcome the drug resistance were reviewed.
- phosphatidylinositol-3-kinase /
- PI3K inhibitors /
- antitumor /
- drug combination /
- resistance

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参考文献(42)

[1]	Lorusso PM.Inhibition of the PI3K/AKT/mTOR pathway in solid tumors[J].J Clin Oncol,2016,34(31):3803-3815.
[2]	Perrotta M, Lembo G, Carnevale D. The multifaceted roles of PI3Kγ in hypertension,vascular biology,and inflammation[J].Int J Mol Sci,2016,17(11):1858-1867.
[3]	Okkenhaug K,Graupera M,Vanhaesebroeck B.Targeting PI3K in cancer:impact on tumor cells,their protective stroma,angiogenesis,and immunotherapy[J].Cancer Discov,2016,6(10):1090-1105.
[4]	Marone R,Cmiljanovic V,Giese B,et al.Targeting phosphoinositide 3-kinase:moving towards therapy[J].Biochim Biophys Acta,2008,1784(1):159-185.
[5]	Vlahos CJ,Matter WF,Hui KY,et al.A specific inhibitor of phosphatidylinositol 3-kinase,2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one(LY294002)[J].J Biol Chem,1994,269(7):5241-5248.
[6]	Ihle NT,Williams R,Chow S,et al.Molecular pharmacology and antitumor activity of PX-866,a novel inhibitor of phosphoinositide-3-kinase signaling[J].Mol Cancer Ther,2004,3(7):763-772.
[7]	Folkes AJ,Ahmadi K,Alderton WK,et al.The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d] pyrimidine(GDC-0941)as a potent,selective,orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer[J].J Med Chem,2008,51(18):5522-5532.
[8]	Maira SM,Stauffer FJ,Furet P,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[J].Mol Cancer Ther,2008,7(7):1851-1863.
[9]	Sutherlin DP,Bao L,Berry M,et al.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].J Med Chem,2011,54(21):7579-7587.
[10]	Yu P,Laird AD,Du X,et al.Characterization of the activity of the PI3K/mTOR inhibitor XL765(SAR245409)in tumor models with diverse genetic alterations affecting the PI3K pathway[J].Mol Cancer Ther,2014,13(5):1078-1091.
[11]	Blajecka K,Borgström A,Arcaro A.Phosphatidylinositol 3-kinase isoforms as novel drug targets.[J].Curr Drug Targets,2011,12(7):1056-1081.
[12]	Hewett YG, Uprety D, Shah BK. Idelalisib- a PI3Kδ targeting agent for B-cell malignancies[J].J Oncol Pharm Pract,2016,22(2):284-288.
[13]	Sabbah DA,Hu J,Zhong HA.Advances in the development of class I phosphoinositide 3-kinase(PI3K)inhibitors[J].Curr Top Med Chem,2015,16(13):1413-1426.
[14]	Rodon J, Dienstmann R, Serra V, et al. Development of PI3K inhibitors:lessons learned from early clinical trials[J].Nat Rev Clin Oncol,2013,10(3):143-153.
[15]	Fruman DA,Rommel C.PI3K and cancer:lessons,challenges and opportunities[J].Nat Rev Drug Discov,2014,13(2):140-156.
[16]	Cao PR,Kong YL,Luo YM,et al.Mechanisms of resistance to PI3K-Akt-mTOR signaling pathway inhibitors[J].Chin Pharm J,2016,51(4):253-258.
[17]	Liu P,Cheng H,Roberts TM,et al.Targeting the phosphoinositide 3-kinase pathway in cancer[J].Nat Rev Drug Discov,2009,8(8):627-644.
[18]	Serra V,Scaltriti M,Prudkin L,et al.PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer[J].Oncogene,2011,30(22):2547-2557.
[19]	Floris G,Wozniak A,Sciot R,et al.A potent combination of the novel PI3K inhibitor,GDC-0941,with imatinib in gastrointestinal stromal tumor xenografts:long-lasting responses after treatment withdrawal[J].Clin Cancer Res,2013,19(3):620-630.
[20]	Pérez-Tenorio G,Alkhori L,Olsson B,et al.PIK3CA mutations and PTEN loss correlate with similar prognostic factors and are not mutually exclusive in breast cancer[J].Clin Cancer Res,2007,13(12):3577-3584.
[21]	Krop IE,Saura C,Ahnert JR,et al.A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2⁺ metastatic breast cancer[C].Meeting of the American-Society-of-Clinical-Oncology,2012.
[22]	Shimizu T,Tolcher AW,Papadopoulos KP,et al.The clinical effect of the dual-targeting strategy involving PI3K/AKT/mTOR and RAS/MEK/ERK pathways in patients with advanced cancer[J].Clin Cancer Res,2012,18(8):2316-2325.
[23]	Wu YL,Maachani UB,Schweitzer M,et al.Dual inhibition of PI3K/AKT and MEK/ERK pathways induces synergistic antitumor effects in diffuse intrinsic pontine glioma cells[J].Transl Oncol,2017,10(2):221-228.
[24]	Engelman JA,Chen L,Tan XH,et al.Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers[J].Nature Med,2008,14(12):1351-1356.
[25]	Wei BR,Michael HT,Halsey CH,et al.Synergistic targeted inhibition of MEK and dual PI3K/mTOR diminishes viability and inhibits tumor growth of canine melanoma underscoring its utility as a preclinical model for human mucosal melanoma[J].Pigment Cell Melanoma Res,2016,29(6):643-655.
[26]	Bedard PL,Tabernero J,Janku F,et al.A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib(BKM120)in combination with the oral MEK1/2 inhibitor trametinib(GSK1120212)in patients with selected advanced solid tumors[J].Clin Cancer Res,2015,21(4):730-738.
[27]	Ilic N,Utermark T,Widlund HR,et al.PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E(eIF4E)axis[J].Proc Natl Acad Sci U S A,2011,108(37):699-708.
[28]	Dawson MA,Prinjha RK,Dittmann A,et al.Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia[J].Nature,2011,478(7370):529-533.
[29]	Mertz JA,Conery AR,Bryant BM,et al.Targeting MYC dependence in cancer by inhibiting BET bromodomains[J].Proc Natl Acad Sci U S A,2011,108(40):16669-16674.
[30]	Stratikopoulos EE,Dendy M,Szabolcs M,et al.Kinase and BET inhibitors together clamp inhibition of PI3K signaling and overcome resistance to therapy[J].Cancer Cell,2015,27(6):837-851.
[31]	Granato M,Rizzello C,Romeo M A,et al.Concomitant reduction of c-Myc expression and PI3K/AKT/mTOR signaling by quercetin induces a strong cytotoxic effect against Burkitt′s lymphoma[J].Int J Biochem Cell B,2016,79:393-400.
[32]	Kumar A,Fernandez-Capetillo O,Carrera AC.Nuclear phosphoinositide 3-kinase beta controls double-strand break DNA repair[J].Proc Natl Acad Sci U S A,2010,107(16):7491-7496.
[33]	Ibrahim YH, Garcíagarcía C, Serra V, et al. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition[J].Cancer Discov,2012,2(11):1036-1047.
[34]	Wang D,Li C,Zhang Y,et al.Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes[J].Gynecol Oncol,2016,142(3):548-556.
[35]	Juvekar A,Burga LN,Hu H,et al.Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer[J].Cancer Discov,2012,2(11):1048-1063.
[36]	Baselga J,Campone M,Piccart M,et al.Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer[J].N Engl J Med,2012,366(6):520-529.
[37]	Miller TW,Balko JM,Arteaga CL.Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer[J].J Clin Oncol,2011,29(33):4452-4461.
[38]	Mayer IA,Fasching PA,Gnant M,et al.Phase II,randomized,placebo-controlled study of BYL719 or buparlisib(BKM120)with letrozole for neoadjuvant treatment of postmenopausal women with HR+/HER2-,PIK3CA mutant or wild-type,breast cancer(BC)[J].J Clin Oncol,2014,32:5s.
[39]	Santarpia L,Lippman SM,Elnaggar AK.Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy[J].Expert Opin Ther Targets,2012,16(1):103-119.
[40]	Coffee EM,Faber AC,Roper J,et al.Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E)colorectal cancer[J].Clin Cancer Res,2013,19(10):2688-2698.
[41]	Davids MS,Deng J,Wiestner A,et al.Decreased mitochondrial apoptotic priming underlies stroma-mediated treatment resistance in chronic lymphocytic leukemia[J].Blood,2012,120(17):3501-3509.
[42]	Rahmani M,Aust MM,Attkisson E,et al.Dual inhibition of Bcl-2 and Bcl-xL strikingly enhances PI3K inhibition-induced apoptosis in human myeloid leukemia cells through a GSK3- and Bim-dependent mechanism[J].Cancer Res,2012,73(4):1340-1351.