Personalized and Precision Medicine Journal
Where Innovations Meets Personalized and Precision Medicine

Introducing PROTAC Therapy—a Novel Tailored Approach to Lung Cancer Treatment

Document Type : Review Article

Authors

Sahar Abareshi 1
Yeganeh Yousefi 2
Niusha Zeynalniya Toosi 2

1 Department of biology, Faculty of science, Mashhad branch, Islamic Azad University, Mashhad, Iran

2 Department of biology, Faculty of science, Mashhad branch, Islamic Azad University, Mashhad, Iran.

https://doi.org/10.22034/pmj.2024.712171
Abstract
Drug resistance in cancer is a major challenge to properly treating malignancy. Therapies aimed at proteins involved in cancer development may become less effective due to acquired resistance to medications, often resulting from mutations as well as heightened expression of the targeted proteins. Posttranslational modifications (PTMs) like as phosphorylation, methylation, ubiquitination, and acetylation are crucial for regulating protein expression levels. PROTACs are engineered to selectively degrade a specific protein of interest (POI) by ubiquitination, resulting in a regulated decrease in the POI’s expression. PROTACs show great potential in targeting hitherto untargetable proteins, such as various transcription factors. PROTACs enhance antitumor immune therapy by specifically modifying certain proteins. Although molecular therapies have advanced, lung cancer remains a major contributor to cancer-related mortality. The management of those with lung cancer is now limited by a lack of targeted therapy choices and the development of acquired drug resistance. Using the intracellular ubiquitin-proteasome system for directed protein breakdown might enhance individualized treatment for lung cancer patients. This study explores the rationale for using PROTAC therapy as an innovative specific therapy and the current advancements in PROTAC development for lung tumors.

Keywords

Cancer
Drug resistance
Targeted therapy
PROTAC therapy
  1. Bade, B. C., & Cruz, C. S. D. (2020). Lung cancer 2020: epidemiology, etiology, and prevention. Clinics in chest medicine, 41(1), 1-24.
  2. Thandra, K. C., Barsouk, A., Saginala, K., Aluru, J. S., & Barsouk, A. (2021). Epidemiology of lung cancer. Contemporary Oncology/Współczesna Onkologia, 25(1), 45-52.
  3. Ganti, A. K., Klein, A. B., Cotarla, I., Seal, B., & Chou, E. (2021). Update of incidence, prevalence, survival, and initial treatment in patients with non–small cell lung cancer in the US. JAMA oncology, 7(12), 1824-1832.
  4. Leiter, A., Veluswamy, R. R., & Wisnivesky, J. P. (2023). The global burden of lung cancer: current status and future trends. Nature Reviews Clinical Oncology, 20(9), 624-639.
  5. Zhang, Y., Vaccarella, S., Morgan, E., Li, M., Etxeberria, J., Chokunonga, E., ... & Bray, F. (2023). Global variations in lung cancer incidence by histological subtype in 2020: a population-based study. The Lancet Oncology, 24(11), 1206-1218.
  6. Gockel, L. M., Pfeifer, V., Baltes, F., Bachmaier, R. D., Wagner, K. G., Bendas, G., ... & Steinebach, C. (2022). Design, synthesis, and characterization of PROTACs targeting the androgen receptor in prostate and lung cancer models. Archiv der Pharmazie, 355(5), 2100467.
  7. Petty, W. J., & Paz-Ares, L. (2023). Emerging strategies for the treatment of small cell lung cancer: a review. JAMA oncology, 9(3), 419-429.
  8. Liu, W. J., Du, Y., Wen, R., Yang, M., & Xu, J. (2020). Drug resistance to targeted therapeutic strategies in non-small cell lung cancer. Pharmacology & therapeutics, 206, 107438.
  9. Passaro, A., Brahmer, J., Antonia, S., Mok, T., & Peters, S. (2022). Managing resistance to immune checkpoint inhibitors in lung cancer: treatment and novel strategies. Journal of Clinical Oncology.
  10. Wang, K., & Zhou, H. (2021). Proteolysis targeting chimera (PROTAC) for epidermal growth factor receptor enhances anti‐tumor immunity in non‐small cell lung cancer. Drug Development Research, 82(3), 422-429.
  11. He, S., Ma, J., Fang, Y., Liu, Y., Wu, S., Dong, G., ... & Sheng, C. (2021). Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer. Acta Pharmaceutica Sinica B, 11(6), 1617-1628.
  12. Li, J. W., Zheng, G., Kaye, F. J., & Wu, L. (2023). PROTAC therapy as a new targeted therapy for lung cancer. Molecular Therapy, 31(3), 647-656.
  13. Qi, S. M., Dong, J., Xu, Z. Y., Cheng, X. D., Zhang, W. D., & Qin, J. J. (2021). PROTAC: an effective targeted protein degradation strategy for cancer therapy. Frontiers in Pharmacology, 12, 692574.
  14. Qi, S. M., Dong, J., Xu, Z. Y., Cheng, X. D., Zhang, W. D., & Qin, J. J. (2021). PROTAC: an effective targeted protein degradation strategy for cancer therapy. Frontiers in Pharmacology, 12, 692574.
  15. Liu, J., Ma, J., Liu, Y., Xia, J., Li, Y., Wang, Z. P., & Wei, W. (2020, December). PROTACs: A novel strategy for cancer therapy. In Seminars in Cancer Biology(Vol. 67, pp. 171-179). Academic Press.
  16. Zhou, X., Dong, R., Zhang, J. Y., Zheng, X., & Sun, L. P. (2020). PROTAC: A promising technology for cancer treatment. European journal of medicinal chemistry, 203, 112539.
  17. Kelm, J. M., Pandey, D. S., Malin, E., Kansou, H., Arora, S., Kumar, R., & Gavande, N. S. (2023). PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy. Molecular Cancer, 22(1), 62.
  18. Kelm, J. M., Pandey, D. S., Malin, E., Kansou, H., Arora, S., Kumar, R., & Gavande, N. S. (2023). PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy. Molecular Cancer, 22(1), 62.
  19. Han, X., & Sun, Y. (2022). Strategies for the discovery of oral PROTAC degraders aimed at cancer therapy. Cell Reports Physical Science.
  20. Farnaby, W., Koegl, M., McConnell, D. B., & Ciulli, A. (2021). Transforming targeted cancer therapy with PROTACs: A forward-looking perspective. Current opinion in pharmacology, 57, 175-183.
  21. Békés, M., Langley, D. R., & Crews, C. M. (2022). PROTAC targeted protein degraders: the past is prologue. Nature Reviews Drug Discovery, 21(3), 181-200.
  22. Burke, M. R., Smith, A. R., & Zheng, G. (2022). Overcoming cancer drug resistance utilizing PROTAC technology. Frontiers in Cell and Developmental Biology, 10, 872729.
  23. Zhang, H. T., Peng, R., Chen, S., Shen, A., Zhao, L., Tang, W., ... & Zhang, L. (2022). Versatile Nano‐PROTAC‐Induced Epigenetic Reader Degradation for Efficient Lung Cancer Therapy. Advanced Science, 9(29), 2202039.
  24. Zhang, H., Zhao, H. Y., Xi, X. X., Liu, Y. J., Xin, M., Mao, S., ... & Zhang, S. Q. (2020). Discovery of potent epidermal growth factor receptor (EGFR) degraders by proteolysis targeting chimera (PROTAC). European Journal of Medicinal Chemistry, 189, 112061.
  25. Zhao, H. Y., Wang, H. P., Mao, Y. Z., Zhang, H., Xin, M., Xi, X. X., ... & Zhang, S. Q. (2022). Discovery of potent PROTACs targeting EGFR mutants through the optimization of covalent EGFR ligands. Journal of medicinal chemistry, 65(6), 4709-4726.
  26. Zhao, H. Y., Yang, X. Y., Lei, H., Xi, X. X., Lu, S. M., Zhang, J. J., ... & Zhang, S. Q. (2020). Discovery of potent small molecule PROTACs targeting mutant EGFR. European Journal of Medicinal Chemistry, 208, 112781.
  27. Zhao, H. Y., Wang, H. P., Mao, Y. Z., Zhang, H., Xin, M., Xi, X. X., ... & Zhang, S. Q. (2022). Discovery of potent PROTACs targeting EGFR mutants through the optimization of covalent EGFR ligands. Journal of medicinal chemistry, 65(6), 4709-4726.
  28. Du, Y., Chen, Y., Wang, Y., Chen, J., Lu, X., Zhang, L., ... & Zhang, G. (2022). HJM-561, a potent, selective, and orally bioavailable EGFR PROTAC that overcomes osimertinib-resistant EGFR triple mutations. Molecular Cancer Therapeutics, 21(7), 1060-1066.
  29. Shi, S., Du, Y., Zou, Y., Niu, J., Cai, Z., Wang, X., ... & Zhu, Q. (2022). Rational design for nitroreductase (NTR)-responsive proteolysis targeting chimeras (PROTACs) selectively targeting tumor tissues. Journal of Medicinal Chemistry, 65(6), 5057-5071.
  30. Zhang, W., Li, P., Sun, S., Jia, C., Yang, N., Zhuang, X., ... & Li, S. (2022). Discovery of highly potent and selective CRBN-recruiting EGFRL858R/T790M degraders in vivo. European Journal of Medicinal Chemistry, 238, 114509.
  31. Li, K., & Crews, C. M. (2022). PROTACs: past, present and future. Chemical Society Reviews, 51(12), 5214-5236.
  32. Liu, J., Xue, L., Xu, X., Luo, J., & Zhang, S. (2021). FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer. Experimental Cell Research, 408(2), 112868.
  33. Hyun, S., & Shin, D. (2021). Small-molecule inhibitors and degraders targeting KRAS-driven cancers. International Journal of Molecular Sciences, 22(22), 12142.
  34. Yang, F., Wen, Y., Wang, C., Zhou, Y., Zhou, Y., Zhang, Z. M., ... & Lu, X. (2022). Efficient targeted oncogenic KRASG12C degradation via first reversible-covalent PROTAC. European Journal of Medicinal Chemistry, 230, 114088.
  35. Bond, M. J., Chu, L., Nalawansha, D. A., Li, K., & Crews, C. M. (2020). Targeted Degradation of Oncogenic KRASG12Cby VHL-Recruiting PROTACs. ACS central science, 6(8), 1367–1375.
  36. Jiang, Z., Li, Y., Zhou, X., Wen, J., Zheng, P., & Zhu, W. (2024). Research Progress on Small Molecule Inhibitors Targeting KRAS G12C with Acrylamide Structure and the Strategies for Solving KRAS Inhibitor Resistance. Bioorganic & Medicinal Chemistry, 117627.
  37. Yan, G., Zhong, X., Yue, L., Pu, C., Shan, H., Lan, S., ... & Li, R. (2021). Discovery of a PROTAC targeting ALK with in vivo activity. European Journal of Medicinal Chemistry, 212, 113150.
  38. Liu, J., Xue, L., Xu, X., Luo, J., & Zhang, S. (2021). FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer. Experimental Cell Research, 408(2), 112868.
  39. Gao, H., Zhang, J. Y., Zhao, L. J., & Guo, Y. Y. (2023). Synthesis and clinical application of small-molecule inhibitors and PROTACs of anaplastic lymphoma kinase. Bioorganic Chemistry, 106807.
  40. Xie S, Sun Y, Liu Y, Li X, Li X, Zhong W, Zhan F, Zhu J, Yao H, Yang DH, Chen ZS, Xu J, Xu S. Development of Alectinib-Based PROTACs as Novel Potent Degraders of Anaplastic Lymphoma Kinase (ALK). J Med Chem. 2021 Jul 8;64(13):9120-9140.
  41. Zhang, C., Han, X. R., Yang, X., Jiang, B., Liu, J., Xiong, Y., & Jin, J. (2018). Proteolysis targeting chimeras (PROTACs) of anaplastic lymphoma kinase (ALK). European journal of medicinal chemistry, 151, 304-314.
  42. Recondo, G., Mezquita, L., Facchinetti, F., Planchard, D., Gazzah, A., Bigot, L., ... & Friboulet, L. (2020). Diverse resistance mechanisms to the third-generation ALK inhibitor lorlatinib in ALK-rearranged lung cancer. Clinical Cancer Research, 26(1), 242-255.
  43. Song, X., Zhong, H., Qu, X., Yang, L., & Jiang, B. (2021). Two novel strategies to overcome the resistance to ALK tyrosine kinase inhibitor drugs: Macrocyclic inhibitors and proteolysis‐targeting chimeras. MedComm, 2(3), 341-350.
  44. Gao, H., Zheng, C., Du, J., Wu, Y., Sun, Y., Han, C., ... & Rao, Y. (2020). FAK-targeting PROTAC as a chemical tool for the investigation of non-enzymatic FAK function in mice. Protein & Cell, 11(7), 534-539.
  45. Liu, J., Xue, L., Xu, X., Luo, J., & Zhang, S. (2021). FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer. Experimental Cell Research, 408(2), 112868.
  46. Cromm, P. M., Samarasinghe, K. T., Hines, J., & Crews, C. M. (2018). Addressing kinase-independent functions of Fak via PROTAC-mediated degradation. Journal of the American Chemical Society, 140(49), 17019-17026.
  47. Kurim, S. (2018). Towards Novel Effective Combination Therapy for KRAS Mutant Non-Small Cell Lung Cancer(Doctoral dissertation, Université d'Ottawa/University of Ottawa).
  48. Farnaby, W., Koegl, M., McConnell, D. B., & Ciulli, A. (2021). Transforming targeted cancer therapy with PROTACs: A forward-looking perspective. Current opinion in pharmacology, 57, 175-183.
  49. Webb, T., Craigon, C., & Ciulli, A. (2022). Targeting epigenetic modulators using PROTAC degraders: Current status and future perspective. Bioorganic & Medicinal Chemistry Letters, 63, 128653.
  50. Liu, J., Ma, J., Liu, Y., Xia, J., Li, Y., Wang, Z. P., & Wei, W. (2020, December). PROTACs: A novel strategy for cancer therapy. In Seminars in Cancer Biology(Vol. 67, pp. 171-179). Academic Press.
  51. Gao, H., Sun, X., & Rao, Y. (2020). PROTAC technology: opportunities and challenges. ACS medicinal chemistry letters, 11(3), 237-240.
  52. Li, X., & Song, Y. (2020). Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy. Journal of hematology & oncology, 13(1), 1-14.
  53. Chen, X., Shen, H., Shao, Y., Ma, Q., Niu, Y., & Shang, Z. (2021). A narrative review of proteolytic targeting chimeras (PROTACs): future perspective for prostate cancer therapy. Translational Andrology and Urology, 10(2), 954.
  54. Burke, M. R., Smith, A. R., & Zheng, G. (2022). Overcoming cancer drug resistance utilizing PROTAC technology. Frontiers in Cell and Developmental Biology, 10, 872729.
  55. Zhou, X., Dong, R., Zhang, J. Y., Zheng, X., & Sun, L. P. (2020). PROTAC: A promising technology for cancer treatment. European journal of medicinal chemistry, 203, 112539.
  56. Wang, C., Zhang, Y., Xing, D., & Zhang, R. (2021). PROTACs technology for targeting non-oncoproteins: advances and perspectives. Bioorganic Chemistry, 114, 105109.
  57. Chen, C., Yang, Y., Wang, Z., Li, H., Dong, C., & Zhang, X. (2023). Recent Advances in Pro-PROTAC Development to Address On-Target Off-Tumor Toxicity. Journal of Medicinal Chemistry.
  58. Martín-Acosta, P., & Xiao, X. (2021). PROTACs to address the challenges facing small molecule inhibitors. European journal of medicinal chemistry, 210, 112993.
  59. Qi, S. M., Dong, J., Xu, Z. Y., Cheng, X. D., Zhang, W. D., & Qin, J. J. (2021). PROTAC: an effective targeted protein degradation strategy for cancer therapy. Frontiers in Pharmacology, 12, 692574.
  60. Li, Y., Song, J., Zhou, P., Zhou, J., & Xie, S. (2022). Targeting undruggable transcription factors with PROTACs: advances and perspectives. Journal of Medicinal Chemistry, 65(15), 10183-10194.
Personalized and Precision Medicine Journal
Volume 9, Issue 32 - Serial Number 32
Original article
Winter 2024
Pages 29-35

  • Receive Date 02 December 2023
  • Revise Date 29 January 2024
  • Accept Date 15 February 2024

Home

Publication Ethics

Guide for Authors

Submit Manuscript

Contact Us