p-glycoprotein MRP1 ABCG2 anthracycline vinca alkaloids microtubule stabilizing drug (multidrug resistance, MDR) MDR verapamil quinidine cyclos

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1 113 談癌症治療的抗藥性文圖 / 張景明張金堅 * 澄清醫院中港院區血液腫瘤科澄清醫院中港院區外科 * 前言 (chemotherapy) (Paul Ehrlich) (micrometastases) 1960 (monoclonal antibody)(tyrosine kinase inhibitor) 癌症治療藥物發展簡史 George Clowes (transplantable tumor system) 1939 Charles Huggins (1) 2. (nitrogen mustard) Farbermethotrexate Farber (alkylating agent) (antitumor antibiotics) Charles Heidelberger 5-fluorouracil(5- FU) methotrexate (2) 圖 1 常見的抗藥性機轉 (3) (Glivec, imatinib) 1997 Rituximab B (immuno-oncology) anti-pd1 anti- CTLA4 多樣化的腫瘤抗藥性機轉 1 (3) 1. (drug efflux) 1983 Kartner p-glycoprotein permeability glycoprotein P-gp MRP1(multidrug resistance protein 1) ABCB1(ATP-binding cassette sub-family B member 1) Science (4) ATP 2014, Vol.57, No.3 15

2 p-glycoprotein MRP1 ABCG2 anthracycline vinca alkaloids microtubule stabilizing drug (multidrug resistance, MDR) MDR verapamil quinidine cyclosporine (5) 2. (apoptosis pathway) (apoptosis) (programmed cell death)(extrinsic pathway) (intrinsic pathway) c (cytochrome c) (caspase) (pro-apoptotic) Bax (anti-apoptotic) Bcl-2 Bcl-xL IAP(inhibitor of apoptosis protein) (6) BH3(Bcl-2 homology domain 3) (7) Bcl-2, Bcl-xL 3.DNA (DNA repair pathway) DNADNA DNA 3 (direct reversal) DNA (singlestrand DNA repair) ( base excision repair/ber nucleotide excision repair/ NER mismatch repair/mmr) DNA (double-strand DNA repair) homologous recombination/hr non-homologous end joining/nhej (8) (GBM, glioblastoma multiforme) temozolomide DNA MGMT temozolomide temozolomide 4. (microenvironment) (hypoxia) HIF(hypoxia-inducible factor) HIF HIF (epithelialto-mesenchymal transition, EMT) (cell migration)(pre-metastatic niche) (3) (stromal cells) (tumor-associated macrophage, TAM) (angiogenesis) (lymphangiogenesis) (9) (cancerassociated fibroblasts, CAF) 5. (cancer stem cells, CSC) (selfrenewal) (differentiate) p-glycoprotein , Vol.57, No.3

3 115 ABCG2 DNA (10) 6. (activating mutation of oncogenes) (inactivating mutation of tumor suppressor genes) PI3K/Akt/mTOR Ras/Raf/ MAPK NF- B RB PTEN (3) mtor 針對不同癌症間常見的抗藥機轉, 是否有治療策略? 1. (chronic myelogenous leukemia, CML) 100% 9 22 BCR-ABL1 BCR-ABL (oncoprotein) (Glivec) (tyrosine kinase inhibitor, TKI) Drunker ATP BCR-ABL (11) 表 1 酪胺酸激酶抑制劑的抗藥性分類 BCR-ABL1 (poor compliance) (heterogeneity) (ABCB1, ABCG2) BCR-ABL1 BCR-ABL1 BCR-ABL (quiescent stem cells) - (clonal evolution) - Src - (primary resistance) (secondary resistance) 25% 15% 1 BCR-ABL BCR-ABL BCR-ABL 50 BCR- ABL BCR-ABL (a) (b)p- loop(atp ) (c) (catalytic domain) (d)a-loop P-loop (11) Src Src , Vol.57, No.3 17

4 116 BCR-ABL nilotinib dasatinib BCR-ABL T315I T315I ponatinib T315I T315I BCR-ABL 2012 FDA (accelerated approval) (12) ponatinib 2. (breast cancer) HER2 HER2 85% mtor PI3K/AKT/mTOR PI3K PI3K AKT mtorc1(mtor complex 1) mtorc1 4E-BP1 S6K1 4E-BP1 S6K1 ER(estrogen receptor) S6K1 2 PI3K/AKT/mTOR ER PI3K ER PI3K/AKT/mTOR(crosstalk) ER PI3K/AKT/mTOR PI3K/AKT/mTOR (13) mtor Johns Hopkins 圖 2 PI3K/AKT/mTOR 路徑與 ER 之間的互相對話 (cross-talk) (13) temsirolimus mtor letrozole letrozole HORIZON (progression free survival, PFS) temsirolimusmtor everolimus TAMRAD everolimus tamoxifen (aromatase inhibitor, AI) 111 everolimus (clinical benefit rate) (time to progression) tamoxifen BOLERO2 (nonsteroidal AI) exemestane + everolimus exemestane + placebo exemestane + everolimus (progression-free survival) exemestane + placebo (14) 3 mtor , Vol.57, No.3

5 117 圖 3 肺癌表皮生長因子受器的突變 (EGFR mutations) (16) PI3K/AKT/mTOR mtor HER2(trastuzumab, Herceptin) HER2 3 (a) HER2( IGF- 1, MET, HER1, HER3) (b) PI3K/AKT/mTOR PIK3CA gain-of-function mutation AKT mutation PTEN loss (c) HER2 (15) BOLERO3 HER2 (locally advanced) Herceptin Herceptin + vinorelbine everolimus mtor vs. 5.8 mtor HER2 HER 3. (non-small cell lung cancer, NSCLC) 2004 (EGFR) (EGFR TKI) gefitinib Iressa erlotinib Tarceva (sensitive mutations) (resistant mutations) 90% 85% exon 19 deletion( 45%) exon 21 L858R 40% gefitinib erlotinib ATP 3 (16) 30-40% EGFR10% ISEL BR.21 EGFR 60-80% EGFR 30-50% IPASS WJTOG3405 NEJ002 OPTIMAL EURATAC EGFR, platinum doublet (response rate) (17) EGFR EGFR 30% (a)(de novo resistant EGFR mutation) exon 20 insertion T790M (b) cytochrome P450 CYP3A4 CYP1A1 erlotinib (polymorphism) CYP3A4 CYP1A1 erlotinib (c) (d) PIK3CA ALK ROS1 RET 2014, Vol.57, No.3 19

6 118 HER2 KRAS BRAF MEK1 (16) (a) (secondsite EGFR mutations)t790m (b) 1-5% (c) EGFR 5-10% MET (MET amplification) MET ERBB3 EGFR EGFR (d) 5% (small cell lung cancer) (18) MET PIK3CA 結語參考文獻 1. DeVita VT, Jr., Chu E: A history of cancer chemotherapy. Cancer Res 2008;68: DeVita VT, Jr., Rosenberg SA: Two hundred years of cancer research. N Engl J Med 2012;366: Rebucci M, Michiels C: Molecular aspects of cancer cell resistance to chemotherapy. Biochem Pharmacol 2013;85: Kartner N, Riordan JR, Ling V: Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 1983;221: Robert J, Jarry C: Multidrug resistance reversal agents. J Med Chem 2003;46: Igney FH, Krammer PH: Death and anti-death: tumour resistance to apoptosis. Nat Rev Cancer 2002;2: Ni Chonghaile T, Letai A: Mimicking the BH3 domain to kill cancer cells. Oncogene 2008;27 Suppl 1:S Tell G, Wilson DM, 3rd. Targeting DNA repair proteins for cancer treatment. Cell Mol Life Sci 2010;67: Coffelt SB, Hughes R, Lewis CE: Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochem Biophys Acta 2009;1796: Dean M, Fojo T, Bates S: Tumour stem cells and drug resistance. Nat Rev Cancer 2005;5: Milojkovic D, Apperley J: Mechanisms of resistance to imatinib and second-generation tyrosine inhibitors in chronic myeloid leukemia. Clin Cancer Res 2009;15: Cortes JE, Kim DW, Pinilla-Ibarz J, et al.: A phase 2 trial of ponatinib in philadelphia chromosome-positive leukemias. N Engl J Med 2013;369: Rugo HS, Keck S: Reversing hormone resistance: have we found the golden key? J Clin Oncol 2012;30: Baselga J, Campone M, Piccart M, et al. :Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 2012;366: Puglisi F, Minisini AM, De Angelis C, et al.: Overcoming treatment resistance in HER2-positive breast cancer: potential strategies. Drugs 2012;72: Ohashi K, Maruvka YE, Michor F, et al.: Epidermal growth factor receptor tyrosine kinase inhibitor-resistant disease. J Clin Oncol 2013;31: Antonicelli A, Cafarotti S, Indini A, et al.: EGFR-targeted therapy for non-small cell lung cancer: focus on EGFR oncogenic mutation. Int J Med Sci 2013;10: Sequist LV, Waltman BA, Dias-Santagata D, et al.: Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra , Vol.57, No.3

抗肿瘤药理学网课件xjwang.ppt

抗肿瘤药理学网课件xjwang.ppt 2016-11-04 cytotoxic agents Cell Cycle-nonspecific (CCNS) agents Alkylating agents Carmustine Chlorambucil, Melphalan, Cyclophosphamide, Thiotepa Anthracyclines Daunorubicin, Doxorubicin, Epirubicin