Таргетная терапия: новые мишени, перспективы и клиническое применение

Обложка


Цитировать

Полный текст

Открытый доступ Открытый доступ
Доступ закрыт Доступ предоставлен
Доступ закрыт Доступ платный или только для подписчиков

Аннотация

Рак продолжает оставаться одной из ведущих причин смертности в мире, и его гетерогенность создаёт значительные сложности в разработке эффективных терапевтических подходов. Современные достижения в молекулярной биологии и иммунологии открывают возможности для создания высокоизбирательных методов лечения, направленных на специфические молекулярные мишени опухолевых клеток. В данном обзоре рассматриваются новейшие достижения в таргетной терапии рака, включая применение протеолиз-таргетирующих химер (PROTACs) для деградации онкогенных белков, ингибирование сигнального пути PI3K/AKT/mTOR, разработку антитело-препаратных конъюгатов с фокусом на сацитузумаб говитекан и датопотамаб дерукстекан, а также перспективы CAR-T-клеточной терапии, нацеленной на антигены, такие как BCMA. Особое внимание уделено роли экспортинов, особенно XPO1, как потенциальных мишеней для преодоления лекарственной резистентности. Обсуждаются текущие клинические испытания, успехи и возникающие сложности при внедрении этих инновационных терапевтических подходов. Уникальность данного обзора заключается в комплексном анализе передовых таргетных стратегий и иммунотерапий, которые обладают потенциалом значительно улучшить исходы лечения и качество жизни пациентов с различными формами рака. Направление на преодоление резистентности и оптимизация терапевтических стратегий обещают дальнейшее повышение эффективности онкологической терапии и улучшение качества жизни пациентов.

Полный текст

Доступ закрыт

Об авторах

Виктория Романовна Курьянова

Карагандинский медицинский университет

Автор, ответственный за переписку.
Email: kuryanova-viktoriya@mail.ru
ORCID iD: 0009-0002-0105-9285
SPIN-код: 3553-0929
Казахстан, Караганда

Феруза Болатовна Гусейнова

Карагандинский медицинский университет

Email: f.gusejnova.99@mail.ru
ORCID iD: 0009-0005-1410-2600
Казахстан, Караганда

Айгерим Еркингелдиевна Нуркелдина

Карагандинский медицинский университет

Email: aiheros.1d@gmail.com
ORCID iD: 0009-0006-6829-5249
Казахстан, Караганда

Виталий Юрьевич Салафетов

Карагандинский медицинский университет

Email: salafetov@icloud.com
ORCID iD: 0009-0003-8985-4757
Казахстан, Караганда

Список литературы

  1. Bray F, Laversanne M, Sung H, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74(3):229–263. doi: 10.3322/caac.21834
  2. Yao T, Xiao H, Wang H, Xu X. Recent advances in PROTACs for drug targeted protein research. Int J Mol Sci. 2022;23(18):10328. doi: 10.3390/ijms231810328
  3. Crews CM, Hu Z. Recent developments in PROTAC-mediated protein degradation: From bench to clinic. Chembiochem. 2021;22(14):2107–2116. doi: 10.1002/cbic.202100270
  4. Peng Y, Wang Y, Zhou C, et al. PI3K/AKT/MTOR pathway and its role in cancer therapeutics: Are we making headway? Front Oncol. 2022;12:819128. doi: 10.3389/fonc.2022.819128
  5. Rugo HS, Bardia A, Marmé F, et al. Overall survival with sacituzumab govitecan in hormone receptor-positive and human epidermal growth factor receptor 2-negative metastatic breast cancer (TROPiCS-02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;402(10411):1423–1433. doi: 10.1016/S0140-6736(23)01245-X
  6. Zhang X, Zhang H, Lan H, et al. CAR-T cell therapy in multiple myeloma: Current limitations and potential strategies. Front Immunol. 2023;14:1101495. doi: 10.3389/fimmu.2023.1101495
  7. Martino EA, Vigna E, Bruzzese A, et al. Selinexor in multiple myeloma. Expert Opin Pharmacother. 2024;25(4):421–434. doi: 10.1080/14656566.2024.2333376
  8. Kim E, Mordovkina DA, Sorokin A. Targeting XPO1-Dependent Nuclear Export in Cancer. Biochemistry (Mosc). 2022;87(Suppl1):S178–S191. doi: 10.1134/S0006297922140140
  9. Alzofon N, Jimeno A. Capmatinib for non-small cell lung cancer. Drugs Today (Barc). 2021;57(1):17–25. doi: 10.1358/dot.2021.57.1.3239638
  10. Hadoux J, Elisei R, Brose MS, et al. Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer. N Engl J Med. 2023;389(20):1851–1861. doi: 10.1056/NEJMoa2309719
  11. Petrylak DP, Gao X, Vogelzang NJ, et al. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients with metastatic castrate-resistant prostate cancer following enzalutamide and/or abiraterone. J Clin Oncol. 2020;38(15_suppl):3500. doi: 10.1200/JCO.2020.38.15_suppl.3500
  12. Bai L, Zhou H, Xu R, et al. A potent and selective small-molecule degrader of STAT3 achieves complete tumor regression in vivo. Cancer Cell. 2019;36(5):498–511.e17. doi: 10.1016/j.ccell.2019.10.002
  13. Cantrill C, Chaturvedi P, Rynn C, et al. Fundamental aspects of DMPK optimization of targeted protein degraders. Drug Discov Today. 2020;25(6):969–982. doi: 10.1016/j.drudis.2020.03.012
  14. Zhang L, Riley-Gillis B, Vijay P, Shen Y. Acquired resistance to BET-PROTACs (proteolysis-targeting chimeras) caused by genomic alterations in core components of E3 ligase complexes. Mol Cancer Ther. 2019;18(7):1302–1311. doi: 10.1158/1535-7163.MCT-18-1129
  15. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul. 2006;46:249–279. doi: 10.1016/j.advenzreg.2006.01.004
  16. Malik SN, Brattain M, Ghosh PM, et al. Immunohistochemical demonstration of phospho-Akt in high Gleason grade prostate cancer. Clin Cancer Res. 2002;8(4):1168–1171.
  17. Agarwal AK. How to explain the AKT phosphorylation of downstream targets in the wake of recent findings. Proc Natl Acad Sci U S A. 2018;115(27):E6099–E6100. doi: 10.1073/pnas.1808461115
  18. Davis NM, Sokolosky M, Stadelman K, et al. Deregulation of the EGFR/PI3K/PTEN/Akt/mTORC1 pathway in breast cancer: possibilities for therapeutic intervention. Oncotarget. 2014;5(13):4603–4650. doi: 10.18632/oncotarget.2209
  19. Tsai PJ, Lai YH, Manne RK, et al. Akt: a key transducer in cancer. J Biomed Sci. 2022;29(1):76. doi: 10.1186/s12929-022-00860-9
  20. Hermida MA, Dinesh Kumar J, Leslie NR. GSK3 and its interactions with the PI3K/AKT/mTOR signalling network. Adv Biol Regul. 2017;65:5–15. doi: 10.1016/j.jbior.2017.06.003
  21. Lipinski M, Parks DR, Rouse RV, Herzenberg LA. Human trophoblast cell-surface antigens defined by monoclonal antibodies. Proc Natl Acad Sci U S A. 1981;78(8):5147–5150. doi: 10.1073/pnas.78.8.5147
  22. Trerotola M, Cantanelli P, Guerra E, et al. Upregulation of Trop-2 quantitatively stimulates human cancer growth. Oncogene. 2013;32(2):222–233. doi: 10.1038/onc.2012.36
  23. El ST, Fornaro M, Alberti S. Cloning of the murine TROP2 gene: conservation of a PIP2-binding sequence in the cytoplasmic domain of TROP-2. Int J Cancer. 1998;75(2):324–330. doi: 10.1002/(SICI)1097-0215(19980119)75:2<324::AID-IJC24>3.0.CO;2-B
  24. Ripani E, Sacchetti A, Corda D, Alberti S. Human Trop-2 is a tumor-associated calcium signal transducer. Int J Cancer. 1998;76(5):671–676. doi: 10.1002/(SICI)1097-0215(19980529)76:5<671::AID-IJC10>3.0.CO;2-7
  25. Zaman S, Jadid H, Denson AC, Gray JE. Targeting Trop-2 in solid tumors: future prospects. Onco Targets Ther. 2019;12:1781–1790. doi: 10.2147/OTT.S162447
  26. Cubas R, Zhang S, Li M, et al. Trop2 expression contributes to tumor pathogenesis by activating the ERK MAPK pathway. Mol Cancer. 2010;9:253. doi: 10.1186/1476-4598-9-253
  27. Guerra E, Trerotola M, Dell’Armi V, et al. Trop-2 induces tumor growth through AKT and determines sensitivity to AKT inhibitors. Clin Cancer Res. 2016;22(16):4197–4205. doi: 10.1158/1078-0432.CCR-15-1701
  28. Lin JC, Wu YY, Wu JY, et al. TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma. EMBO Mol Med. 2012;4(6):472–485. doi: 10.1002/emmm.201200222
  29. Trerotola M, Li J, Alberti S, Languino LR. Trop-2 inhibits prostate cancer cell adhesion to fibronectin through the β1 integrin-RACK1 axis. J Cell Physiol. 2012;227(10):3670–3677. doi: 10.1002/jcp.24074
  30. Mori Y, Akita K, Ojima K, et al. Trophoblast cell surface antigen 2 (Trop-2) phosphorylation by protein kinase C α/δ (PKCα/δ) enhances cell motility. J Biol Chem. 2019;294(30):11513–11524. doi: 10.1074/jbc.RA119.008084
  31. Drago JZ, Modi S, Chandarlapaty S. Unlocking the potential of antibody–drug conjugates for cancer therapy. Nat Rev Clin Oncol. 2021;18(6):327–344. doi: 10.1038/s41571-021-00470-8
  32. Bargh JD, Isidro-Llobet A, Parker JS, Spring DR. Cleavable linkers in antibody–drug conjugates. Chem Soc Rev. 2019;48(16):4361–4374. doi: 10.1039/C8CS00676H
  33. Cardillo TM, Govindan SV, Sharkey RM, et al. Sacituzumab Govitecan (IMMU-132), an Anti-Trop-2/SN-38 Antibody-Drug Conjugate: Characterization and Efficacy in Pancreatic, Gastric, and Other Cancers. Bioconjug Chem. 2015;26(5):919–931. doi: 10.1021/acs.bioconjchem.5b00223
  34. Fenn KM, Kalinsky K. Sacituzumab govitecan: antibody–drug conjugate in triple-negative breast cancer and other solid tumors. Drugs Today (Barc). 2019;55(9):575–585. doi: 10.1358/dot.2019.55.9.3039669
  35. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529–1541. doi: 10.1056/NEJMoa2028485
  36. Okajima D, Yasuda S, Maejima T, et al. Datopotamab deruxtecan, a novel TROP2-directed antibody–drug conjugate, demonstrates potent antitumor activity by efficient drug delivery to tumor cells. Mol Cancer Ther. 2021;20(12):2329–2340. doi: 10.1158/1535-7163.MCT-21-0206
  37. Bardia A, O’Shaughnessy J, Moroose RL, et al. Abstract P6-10-03: Datopotamab deruxtecan (Dato-DXd) in advanced triple-negative breast cancer (TNBC): updated results from the phase 1 TROPION-PanTumor01 study. Cancer Res. 2023;83(5Suppl):P6-10-03. doi: 10.1158/1538-7445.SABCS22-P6-10-03
  38. Giugliano F, Corti C, Tarantino P, et al. Bystander effect of antibody–drug conjugates: fact or fiction? Curr Oncol Rep. 2022;24(7):809–817. doi: 10.1007/s11912-022-01266-4
  39. Gerber HP, Sapra P, Loganzo F, May C. Combining antibody–drug conjugates and immune-mediated cancer therapy: what to expect? Biochem Pharmacol. 2016;102:1–6. doi: 10.1016/j.bcp.2015.12.008
  40. Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72. doi: 10.1146/annurev-immunol-032712-100008
  41. Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules. 2020;25(20):4764. doi: 10.3390/molecules25204764
  42. Fu Z, Li S, Han S, et al. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7(1):93. doi: 10.1038/s41392-022-00947-7
  43. Kriegsmann K, Kriegsmann M, Cremer M, et al. Cell-based immunotherapy approaches for multiple myeloma. Br J Cancer. 2019;120(1):38–44. doi: 10.1038/s41416-018-0346-9
  44. Ma T, Shi J, Liu H. Chimeric antigen receptor T cell targeting B cell maturation antigen immunotherapy is promising for multiple myeloma. Ann Hematol. 2019;98(4):813–822. doi: 10.1007/s00277-018-03592-9
  45. Dispenzieri A, Soof CM, Rajkumar V, et al. Serum BCMA levels to predict outcomes for patients with MGUS and smoldering multiple myeloma (SMM). J Clin Oncol. 2019;37(15Suppl):8020. doi: 10.1200/JCO.2019.37.15_suppl.8020
  46. Chen H, Li M, Xu N, et al. Serum B-cell maturation antigen (BCMA) reduces binding of anti-BCMA antibody to multiple myeloma cells. Leuk Res. 2019;81:62–66. doi: 10.1016/j.leukres.2019.04.008
  47. Raje N, Berdeja J, Lin Y, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–1737. doi: 10.1056/NEJMoa1817226
  48. Trudel S, Lendvai N, Popat R, et al. Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019;9(4):37. doi: 10.1038/s41408-019-0196-6
  49. Topp MS, Duell J, Zugmaier G, et al. Anti–B-cell maturation antigen BiTE molecule AMG 420 induces responses in multiple myeloma. J Clin Oncol. 2020;38(8):775–783. doi: 10.1200/JCO.19.01494
  50. Gavriatopoulou M, Ntanasis-Stathopoulos I, Dimopoulos MA, Terpos E. Anti-BCMA antibodies in the future management of multiple myeloma. Expert Rev Anticancer Ther. 2019;19(4):319–326. doi: 10.1080/14737140.2019.1586539
  51. Aladhraei M, Al-Thobhani AK, Poungvarin N, Suwannalert P. Association of XPO1 overexpression with NF-kappaB and Ki67 in colorectal cancer. Asian Pac J Cancer Prev. 2019;20(12):3747–3754. doi: 10.31557/APJCP.2019.20.12.3747
  52. Azizian NG, Li Y. XPO1-dependent nuclear export as a target for cancer therapy. J Hematol Oncol. 2020;13(1):61. doi: 10.1186/s13045-020-00903-w
  53. Chari A, Vogl DT, Gavriatopoulou M, et al. Oral selinexor–dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727–738. doi: 10.1056/NEJMoa1903455
  54. Kalakonda N, Maerevoet M, Cavallo F, et al. Selinexor in patients with relapsed or refractory diffuse large B-cell lymphoma (SADAL): a single-arm, multinational, multicentre, open-label, phase 2 trial. Lancet Haematol. 2020;7(7):e511–e522. doi: 10.1016/S2352-3026(20)30120-4
  55. Bhatnagar B, Zhao J, Kale V, Baz R. Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study. Leuk Lymphoma. 2020;61(2):387–396. doi: 10.1080/10428194.2019.1665664
  56. Khan HY, Wang J, Ezan E, et al. Targeting XPO1 and PAK4 in 8505C anaplastic thyroid cancer cells: putative implications for overcoming lenvatinib therapy resistance. Int J Mol Sci. 2019;21(1):237. doi: 10.3390/ijms21010237
  57. Fujino T, Suda K, Mitsudomi T. Lung Cancer with MET exon 14 Skipping Mutation: Genetic Feature, Current Treatments, and Future Challenges. Lung Cancer (Auckl). 2021;12:35–50. doi: 10.2147/LCTT.S269307
  58. Kim SY, Yin J, Bohlman S, et al. Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing. JTO Clin Res Rep. 2022;3(5):100381. doi: 10.1016/j.jtocrr.2022.100381
  59. Wong SK, Alex D, Bosdet I, et al. MET exon 14 skipping mutation positive non-small cell lung cancer: Response to systemic therapy. Lung Cancer. 2021;154:142–145. doi: 10.1016/j.lungcan.2021.02.030
  60. Remon J, Hendriks LEL, Mountzios G, et al. MET alterations in NSCLC—Current Perspectives and Future Challenges. J Thorac Oncol. 2023;18(4):419–435. doi: 10.1016/j.jtho.2022.10.015
  61. Davies KD, Lomboy A, Lawrence CA, et al. DNA-Based versus RNA-Based Detection of MET Exon 14 Skipping Events in Lung Cancer. J Thorac Oncol. 2019;14(4):737–741. doi: 10.1016/j.jtho.2018.12.020
  62. Rolfo C, Malapelle U, Russo A. Skipping or Not Skipping? That’s the Question! An Algorithm to Classify Novel MET Exon 14 Variants in Non-Small-Cell Lung Cancer. JCO Precis Oncol. 2023;7:e2200674. doi: 10.1200/PO.22.00674
  63. Wolf J, Seto T, Han JY, et al. Capmatinib in MET exon 14-mutated or MET-amplified non-small-cell lung cancer. N Engl J Med. 2020;383(10):944–957. doi: 10.1056/NEJMoa2002787
  64. Paik PK, Felip E, Veillon R, et al. Tepotinib in non-small-cell lung cancer with MET exon 14 skipping mutations. N Engl J Med. 2020;383(10):931–943. doi: 10.1056/NEJMoa2004407
  65. Yao Y, Yang H, Zhu B, et al. Mutations in the MET tyrosine kinase domain and resistance to tyrosine kinase inhibitors in non-small-cell lung cancer. Respir Res. 2023;24(1):28. doi: 10.1186/s12931-023-02329-1
  66. Rivas S, Marín A, Samtani S, et al. MET signaling pathways, resistance mechanisms, and opportunities for target therapies. Int J Mol Sci. 2022;23(22):13898. doi: 10.3390/ijms232213898
  67. Li J, Shang G, Chen YJ, et al. Cryo-EM analyses reveal the common mechanism and diversification in the activation of RET by different ligands. Elife. 2019;8:e47650. doi: 10.7554/eLife.47650
  68. Rich TA, Reckamp KL, Chae YK, et al. Analysis of cell-free DNA from 32,989 advanced cancers reveals novel co-occurring activating RET alterations and oncogenic signaling pathway aberrations. Clin Cancer Res. 2019;25(17):5832–5842. doi: 10.1158/1078-0432.CCR-18-4049
  69. Subbiah V, Yang D, Velcheti V, et al. State-of-the-art strategies for targeting RET-dependent cancers. J Clin Oncol. 2020;38(11):1209–1221. doi: 10.1200/JCO.19.02551
  70. Subbiah V, Hu MI, Wirth LJ, et al. Pralsetinib for patients with advanced or metastatic RET-altered thyroid cancer: results from the ARROW trial. Lancet Diabetes Endocrinol. 2021;9(8):491–501. doi: 10.1016/S2213-8587(21)00120-0
  71. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. N Engl J Med. 2020;383(9):825–835. doi: 10.1056/NEJMoa2005651
  72. Solomon BJ, Tan L, Lin JJ, et al. RET solvent front mutations mediate acquired resistance to selective RET inhibition in RET-driven malignancies. J Thorac Oncol. 2020;15(4):541–549. doi: 10.1016/j.jtho.2020.01.006
  73. Burslem GM, Crews CM. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell. 2020;181(1):102–114. doi: 10.1016/j.cell.2019.11.031

Дополнительные файлы

Доп. файлы
Действие
1. JATS XML
Скачать

© Эко-Вектор, 2024

Ссылка на описание лицензии: https://eco-vector.com/for_authors.php#07
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ПИ № ФС 77 - 86496 от 11.12.2023 г. 
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: ЭЛ № ФС 77 - 80673 от 23.03.2021 г.