PARP抑制剂在小细胞肺癌靶向治疗中的进展

doi:10.3760/cma.j.cn371439-20221123-00073

摘要/Abstract

摘要：

小细胞肺癌（SCLC）是一种发展迅速的恶性肿瘤，具有高度异质性并易产生耐药，预后通常不佳。多聚ADP核糖聚合酶（PARP）抑制剂可靶向作用于DNA损伤反应通路，阻止DNA修复，从而发挥抗肿瘤作用。目前在SCLC治疗方案中既有PARP抑制剂单药治疗，也有与DNA损伤剂或免疫检查点抑制剂联合治疗。尽管目前研究结果有限，但可以看到PARP抑制剂可能是SCLC靶向治疗的突破口。

关键词: 小细胞肺癌, 多（ADP核糖）聚合酶抑制剂, DNA修复, 分子靶向治疗, 靶向制剂

Abstract:

Small cell lung cancer （SCLC） is a rapidly developing malignant tumor，which is highly heterogeneous and prone to drug resistance，and the prognosis is usually poor. Poly ADP-ribose polymerase （PARP） inhibitors target the DNA damage response pathway，preventing DNA repair，thereby exerting anti-tumor effects. Currently，PARP inhibitors are used as monotherapy or in combination with DNA-damaging agents or immune checkpoint inhibitors in the treatment of SCLC. Although the current research results are limited，it can be seen that PARP inhibitors may be a breakthrough in the targeted therapy of SCLC.

Key words: Small cell lung carcinoma, Poly（ADP-ribose） polymerase inhibitors, DNA repair, Molecular targeted therapy, Targeting preparation

刘利, 朱思齐, 孙梦颖, 何敬东. PARP抑制剂在小细胞肺癌靶向治疗中的进展[J]. 国际肿瘤学杂志, 2023, 50(6): 368-372.

Liu Li, Zhu Siqi, Sun Mengying, He Jingdong. Progress of PARP inhibitors in targeted therapy of small cell lung cancer[J]. Journal of International Oncology, 2023, 50(6): 368-372.

参考文献 37

[1]	Ortega-Franco A, Ackermann C, Paz-Ares L, et al. First-line immune checkpoint inhibitors for extensive stage small-cell lung cancer: clinical developments and future directions[J]. ESMO Open, 2021, 6(1): 100003. DOI: 10.1016/j.esmoop.2020.100003. doi: 10.1016/j.esmoop.2020.100003
[2]	Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249. DOI: 10.3322/caac.21660. doi: 10.3322/caac.21660
[3]	Rudin CM, Brambilla E, Faivre-Finn C, et al. Small-cell lung cancer[J]. Nat Rev Dis Primers, 2021, 7(1): 3. DOI: 10.1038/s41572-020-00235-0. doi: 10.1038/s41572-020-00235-0 pmid: 33446664
[4]	Stewart CA, Gay CM, Xi Y, et al. Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer[J]. Nat Cancer, 2020, 1(4): 423-436. DOI: 10.1038/s43018-019-0020-z. doi: 10.1038/s43018-019-0020-z
[5]	Pavan A, Attili I, Pasello G, et al. Immunotherapy in small-cell lung cancer: from molecular promises to clinical challenges[J]. J Immunother Cancer, 2019, 7(1): 205. DOI: 10.1186/s40425-019-0690-1. doi: 10.1186/s40425-019-0690-1 pmid: 31383005
[6]	Lok BH, Gardner EE, Schneeberger VE, et al. PARP inhibitor activity correlates with SLFN11 expression and demonstrates synergy with temozolomide in small cell lung cancer[J]. Clin Cancer Res, 2017, 23(2): 523-535. DOI: 10.1158/1078-0432.CCR-16-1040. doi: 10.1158/1078-0432.CCR-16-1040 pmid: 27440269
[7]	Pietanza MC, Waqar SN, Krug LM, et al. Randomized, double-blind, phase Ⅱ study of temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer[J]. J Clin Oncol, 2018, 36(23): 2386-2394. DOI: 10.1200/JCO.2018.77.7672. doi: 10.1200/JCO.2018.77.7672
[8]	Dias MP, Moser SC, Ganesan S, et al. Understanding and over-coming resistance to PARP inhibitors in cancer therapy[J]. Nat Rev Clin Oncol, 2021, 18(12): 773-791. DOI: 10.1038/s41571-021-00532-x. doi: 10.1038/s41571-021-00532-x
[9]	Zhu H, Wei M, Xu J, et al. PARP inhibitors in pancreatic cancer: molecular mechanisms and clinical applications[J]. Mol Cancer, 2020, 19(1): 49. DOI: 10.1186/s12943-020-01167-9. doi: 10.1186/s12943-020-01167-9 pmid: 32122376
[10]	Cleary JM, Aguirre AJ, Shapiro GI, et al. Biomarker-guided develop-ment of DNA repair inhibitors[J]. Mol Cell, 2020, 78(6): 1070-1085. DOI: 10.1016/j.molcel.2020.04.035. doi: S1097-2765(20)30277-X pmid: 32459988
[11]	Liu S, Hua Y, Wang J, et al. RNA polymerase Ⅲ is required for the repair of DNA double-strand breaks by homologous recombination[J]. Cell, 2021, 184(5): 1314-1329. e10. DOI: 10.1016/j.cell.2021.01.048. doi: 10.1016/j.cell.2021.01.048
[12]	Clements KE, Thakar T, Nicolae CM, et al. Loss of E2F7 confers resistance to poly-ADP-ribose polymerase (PARP) inhibitors in BRCA2-deficient cells[J]. Nucleic Acids Res, 2018, 46(17): 8898-8907. DOI: 10.1093/nar/gky657. doi: 10.1093/nar/gky657 pmid: 30032296
[13]	Engelmann D, Pützer BM. Translating DNA damage into cancer cell death—a roadmap for E2F1 apoptotic signalling and opportunities for new drug combinations to overcome chemoresistance[J]. Drug Resist Updat, 2010, 13(4/5): 119-131. DOI: 10.1016/j.drup.2010.06.001. doi: 10.1016/j.drup.2010.06.001
[14]	Das M. Olaparib provides benefit in metastatic breast cancer[J]. Lancet Oncol, 2017, 18(7): e376. DOI: 10.1016/S1470-2045(17)30453-9. doi: 10.1016/S1470-2045(17)30453-9
[15]	Gunjur A. Talazoparib for BRCA-mutated advanced breast cancer[J]. Lancet Oncol, 2018, 19(10): e511. DOI: 10.1016/S1470-2045(18)30650-8. doi: 10.1016/S1470-2045(18)30650-8
[16]	Owonikoko TK, Dahlberg SE, Khan SA, et al. A phase 1 safety study of veliparib combined with cisplatin and etoposide in extensive stage small cell lung cancer: a trial of the ECOG-ACRIN Cancer Research Group (E2511)[J]. Lung Cancer, 2015, 89(1): 66-70. DOI: 10.1016/j.lungcan.2015.04.015. doi: 10.1016/j.lungcan.2015.04.015 pmid: 25985977
[17]	Owonikoko TK, Dahlberg SE, Sica GL, et al. Randomized phase Ⅱ trial of cisplatin and etoposide in combination with veliparib or placebo for extensive-stage small-cell lung cancer: ECOG-ACRIN 2511 study[J]. J Clin Oncol, 2019, 37(3): 222-229. DOI: 10.1200/JCO.18.00264. doi: 10.1200/JCO.18.00264 pmid: 30523756
[18]	Steffen McLouth LE, Zhao F, Owonikoko TK, et al. Patient-reported tolerability of veliparib combined with cisplatin and etoposide for treatment of extensive stage small cell lung cancer: neurotoxicity and adherence data from the ECOG ACRIN cancer research group E2511 phase Ⅱ randomized trial[J]. Cancer Med, 2020, 9(20): 7511-7523. DOI: 10.1002/cam4.3416. doi: 10.1002/cam4.3416
[19]	Atrafi F, Groen HJM, Byers LA, et al. A phase Ⅰ dose-escalation study of veliparib combined with carboplatin and etoposide in patients with extensive-stage small cell lung cancer and other solid tumors[J]. Clin Cancer Res, 2019, 25(2): 496-505. DOI: 10.1158/1078-0432.CCR-18-2014. doi: 10.1158/1078-0432.CCR-18-2014
[20]	Lazzari C, Gregorc V, Bulotta A, et al. Temozolomide in combination with either veliparib or placebo in patients with relapsed-sensitive or refractory small-cell lung cancer[J]. Transl Lung Cancer Res, 2018, 7(Suppl 4): S329-S333. DOI: 10.21037/tlcr.2018.12.02. doi: 10.21037/tlcr.2018.12.02
[21]	Wahner Hendrickson AE, Menefee ME, Hartmann LC, et al. A phase Ⅰ clinical trial of the poly(ADP-ribose) polymerase inhibitor veliparib and weekly topotecan in patients with solid tumors[J]. Clin Cancer Res, 2018, 24(4): 744-752. DOI: 10.1158/1078-0432.CCR-17-1590. doi: 10.1158/1078-0432.CCR-17-1590 pmid: 29138343
[22]	Farago AF, Yeap BY, Stanzione M, et al. Combination olaparib and temozolomide in relapsed small-cell lung cancer[J]. Cancer Discov, 2019, 9(10): 1372-1387. DOI: DOI: 10.1158/2159-8290.CD-19-0582. doi: 10.1158/2159-8290.CD-19-0582 pmid: 31416802
[23]	Liu JF, Barry WT, Birrer M, et al. Overall survival and updated progression-free survival outcomes in a randomized phase Ⅱ study of combination cediranib and olaparib versus olaparib in relapsed platinum-sensitive ovarian cancer[J]. Ann Oncol, 2019, 30(4): 551-557. DOI: 10.1093/annonc/mdz018. doi: S0923-7534(19)31114-7 pmid: 31987271
[24]	Passiglia F, Reale ML, Cetoretta V, et al. Repositioning PARP inhibitors in the treatment of thoracic malignancies[J]. Cancer Treat Rev, 2021, 99: 102256. DOI: 10.1016/j.ctrv.2021.102256. doi: 10.1016/j.ctrv.2021.102256
[25]	Ai X, Pan Y, Shi J, et al. Efficacy and safety of niraparib as maintenance treatment in patients with extensive-stage SCLC after first-line chemotherapy: a randomized, double-blind, phase 3 study[J]. J Thorac Oncol, 2021, 16(8): 1403-1414. DOI: 10.1016/j.jtho.2021.04.001. doi: 10.1016/j.jtho.2021.04.001
[26]	Mizrahi AG, Hamad H, Gugenheim A, et al. Loss of heterozygosity of BRCA1/2 as a predictive marker for talazoparib response[J]. Anticancer Res, 2022, 42(11): 5257-5263. DOI: 10.21873/anticanres.16032. doi: 10.21873/anticanres.16032 pmid: 36288893
[27]	de Bono J, Ramanathan RK, Mina L, et al. Phase Ⅰ, dose-escalation, two-part trial of the PARP inhibitor talazoparib in patients with advanced germline BRCA1/2 mutations and selected sporadic cancers[J]. Cancer Discov, 2017, 7(6): 620-629. DOI: 10.1158/2159-8290.CD-16-1250. doi: 10.1158/2159-8290.CD-16-1250
[28]	Goldman J, Cummings A, Mendenhall M, et al. OA12.03 Phase 2 study analysis of talazoparib (TALA) plus temozolomide (TMZ) for extensive-stage small cell lung cancer (ES-SCLC)[J]. J Thorac Oncol, 2022, 17(9 Supplement): S32. DOI: 10.1016/j.jtho.2022.07.060. doi: 10.1016/j.jtho.2022.07.060
[29]	Owonikoko TK, Zhang G, Deng X, et al. Poly (ADP) ribose polymerase enzyme inhibitor, veliparib, potentiates chemotherapy and radiation in vitro and in vivo in small cell lung cancer[J]. Cancer Med, 2014, 3(6): 1579-1594. DOI: 10.1002/cam4.317. doi: 10.1002/cam4.317
[30]	Byers LA, Wang J, Nilsson MB, et al. Proteomic profiling identifies dysregulated pathways in small cell lung cancer and novel therapeutic targets including PARP1[J]. Cancer Discov, 2012, 2(9): 798-811. DOI: 10.1158/2159-8290.CD-12-0112. doi: 10.1158/2159-8290.CD-12-0112 pmid: 22961666
[31]	Laird JH, Lok BH, Ma J, et al. Talazoparib is a potent radiosensitizer in small cell lung cancer cell lines and xenografts[J]. Clin Cancer Res, 2018, 24(20): 5143-5152. DOI: 10.1158/1078-0432.CCR-18-0401. doi: 10.1158/1078-0432.CCR-18-0401 pmid: 29945991
[32]	Leal TA, Sharifi MN, Chan N, et al. A phase Ⅰ study of talazoparib (BMN 673) combined with carboplatin and paclitaxel in patients with advanced solid tumors (NCI9782)[J]. Cancer Med, 2022, 11(21): 3969-3981. DOI: 10.1002/cam4.4724. doi: 10.1002/cam4.4724
[33]	Mouw KW, Goldberg MS, Konstantinopoulos PA, et al. DNA damage and repair biomarkers of immunotherapy response[J]. Cancer Discov, 2017, 7(7): 675-693. DOI: 10.1158/2159-8290.CD-17-0226. doi: 10.1158/2159-8290.CD-17-0226 pmid: 28630051
[34]	Slade D. PARP and PARG inhibitors in cancer treatment[J]. Genes Dev, 2020, 34(5/6): 360-394. DOI: 10.1101/gad.334516.119. doi: 10.1101/gad.334516.119
[35]	Sen T, Rodriguez BL, Chen L, et al. Targeting DNA damage response promotes antitumor immunity through STING-mediated T-cell activation in small cell lung cancer[J]. Cancer Discov, 2019, 9(5): 646-661. DOI: 10.1158/2159-8290.CD-18-1020. doi: 10.1158/2159-8290.CD-18-1020 pmid: 30777870
[36]	吴朝真, 张素洁, 胡毅. 奥拉帕尼联合帕博利珠单抗二线治疗广泛期小细胞肺癌的疗效和安全性[J]. 中华肿瘤杂志, 2020, 42(7): 590-593. DOI: 10.3760/cma.j.cn112152-20200319-00226. doi: 10.3760/cma.j.cn112152-20200319-00226
[37]	Thomas A, Vilimas R, Trindade C, et al. Durvalumab in combination with olaparib in patients with relapsed SCLC: results from a phase Ⅱ study[J]. J Thorac Oncol, 2019, 14(8): 1447-1457. DOI: 10.1016/j.jtho.2019.04.026. doi: S1556-0864(19)30361-2 pmid: 31063862