PD-L1 dimerisation induced by biphenyl derivatives mediates anti-breast cancer activity via the non-immune PD-L1–AKT–mTOR/Bcl2 pathway

References

• Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016;13(11):674–690.
   PubMed Web of Science ®Google Scholar
• Emens LA. Breast cancer immunotherapy: facts and hopes. Clin Cancer Res. 2018;24(3):511–520.
   PubMed Web of Science ®Google Scholar
• Li X, Li MH, Lian Z, Zhu H, Kong L, Wang P, Yu J. M. Prognostic role of programmed death ligand-1 expression in breast cancer: a systematic review and meta-analysis. Target Oncol. 2016;11(6):753–761.
   PubMed Web of Science ®Google Scholar
• Bianchini G, De Angelis C, Licata L, Gianni L. Treatment landscape of triple-negative breast cancer – expanded options, evolving needs. Nat Rev Clin Oncol. 2022;19(2):91–113.
   PubMed Web of Science ®Google Scholar
• Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med. 1999;5(12):1365–1369.
   PubMed Web of Science ®Google Scholar
• Fagerberg L, Hallström BM, Oksvold P, Kampf C, Djureinovic D, Odeberg J, Habuka M, Tahmasebpoor S, Danielsson A, Edlund K, et al. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2014;13(2):397–406.
   PubMed Web of Science ®Google Scholar
• Kataoka K. Genetic alterations involving PD-L1/PD-L2 in human malignancies. Gan to Kagaku Ryoho. 2019;46:841–844.
   PubMedGoogle Scholar
• Wang SD, Bajorath J, Flies DB, Dong HD, Honjo T, Chen LP. Molecular modeling and functional mapping of B7-H1 and B7-DC uncouple costimulatory function from PD-1 interaction. J Exp Med. 2003;197(9):1083–1091.
   PubMed Web of Science ®Google Scholar
• Aghbash PS, Eslami N, Shamekh A, Entezari-Maleki T, Baghi HB. SARS-CoV-2 infection: the role of PD-1/PD-L1 and CTLA-4 axis. Life Sci. 2021;270:119124.
   PubMed Web of Science ®Google Scholar
• Zuazo M, Arasanz H, Granda MJG, Bocanegra AI, Fernández-Hinojal G, Gato-Cañas M, Aguillo MM, Marín BH, Teijeira L, Ruiz IM, et al. Functional systemic CD4 immunity is required for clinical responses to PD-L1/PD-1 blockade therapy. Ann Oncol. 2019;30:v504.
   Web of Science ®Google Scholar
• Wang T, Cai S, Cheng Y, Zhang W, Wang M, Sun H, Guo B, Li Z, Xiao Y, Jiang S, et al. Discovery of small-molecule inhibitors of the PD-1/PD-L1 axis that promote pd-l1 internalization and degradation. J Med Chem. 2022;65(5):3879–3893.
   PubMed Web of Science ®Google Scholar
• Zhan MM, Hu XQ, Liu XX, Ruan BF, Xu J, Liao C. From monoclonal antibodies to small molecules: the development of inhibitors targeting the PD-1/PD-L1 pathway. Drug Discov Today. 2016;21(6):1027–1036.
   PubMed Web of Science ®Google Scholar
• Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, Postow MA, Wolchok JD. Toxicities of the anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2016;27(7):1362.
   PubMed Web of Science ®Google Scholar
• Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, Schuster SJ, Millenson MM, Cattry D, Freeman GJ, et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin’s lymphoma. N Engl J Med. 2015;372(4):311–319.
   PubMed Web of Science ®Google Scholar
• Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Kurata T, Chiappori A, Lee KH, de Wit M, et al. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342–2350.
   PubMed Web of Science ®Google Scholar
• Glazar DJ, Johnson M, Farinhas J, Steuer CE, Saba NF, Bonomi M, Chung CH, Enderling H. Early response dynamics predict treatment failure in patients with recurrent and/or metastatic head and neck squamous cell carcinoma treated with cetuximab and nivolumab. Oral Oncol. 2022;127:105787.
   PubMed Web of Science ®Google Scholar
• Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–1813.
   PubMed Web of Science ®Google Scholar
• Muro K, Chung HC, Shankaran V, Geva R, Catenacci D, Gupta S, Eder JP, Golan T, Le DT, Burtness B, et al. Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): a multicentre, open-label, phase 1b trial. Lancet Oncol. 2016;17(6):717–726.
   PubMed Web of Science ®Google Scholar
• Neal JW, Kundu P, Tanaka T, Enquist I, Patel S, Balestrini A, Wang J, Newsom-Davis T, Goto Y, Pavlakis N, et al. CONTACT-01: a phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy. JCO. 2021;39(15_suppl):TPS9134–TPS9134.
   Google Scholar
• Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, Gottfried M, Peled N, Tafreshi A, Cuffe S, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–1833.
   PubMed Web of Science ®Google Scholar
• Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, OAK Study Group, et al. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial (vol 389, pg 255, 2016). Lancet. 2017;389(10066):255–265.
   PubMed Web of Science ®Google Scholar
• Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372(26):2521–2532.
   PubMed Web of Science ®Google Scholar
• Zhao PF, Li L, Jiang XY, Li Q. Mismatch repair deficiency/microsatellite instability-high as a predictor for anti-PD-1/PD-L1 immunotherapy efficacy. J Hematol Oncol. 2019;12(1):54.
   Google Scholar
• Zhou C, Wang Z, Sun Y, Cao L, Ma Z, Wu R, Yu Y, Yao W, Chang J, Chen J, et al. Sugemalimab versus placebo, in combination with platinum-based chemotherapy, as first-line treatment of metastatic non-small-cell lung cancer (GEMSTONE-302): interim and final analyses of a double-blind, randomised, phase 3 clinical trial. Lancet Oncol. 2022;23(2):220–233.
   PubMed Web of Science ®Google Scholar
• Awadasseid A, Wu YL, Zhang W. Advance investigation on synthetic small-molecule inhibitors targeting PD-1/PD-L1 signaling pathway. Life Sci. 2021;282:119813.
   PubMed Web of Science ®Google Scholar
• Lim KH, Suresh B, Park JH, Kim YS, Ramakrishna S, Baek KH. Ubiquitin-specific protease 11 functions as a tumor suppressor by modulating Mgl-1 protein to regulate cancer cell growth. Oncotarget. 2016;7(12):14441–14457.
   PubMedGoogle Scholar
• Lin X, Lu X, Luo G, Xiang H. Progress in PD-1/PD-L1 pathway inhibitors: from biomacromolecules to small molecules. Eur J Med Chem. 2020;186:111876.
   PubMed Web of Science ®Google Scholar
• Chupak LS, Zheng X. Preparation of compounds useful as immunomodulators. 2015.
   Google Scholar
• Liu L, Yao Z, Wang S, Xie T, Wu G, Zhang H, Zhang P, Wu Y, Yuan H, Sun H, et al. Syntheses, biological evaluations, and mechanistic studies of benzo[c][1,2,5]oxadiazole derivatives as potent pd-l1 inhibitors with in vivo antitumor activity. J Med Chem. 2021;64(12):8391–8409.
   PubMed Web of Science ®Google Scholar
• Hou J, Zhao R, Xia W, Chang C-W, You Y, Hsu J-M, Nie L, Chen Y, Wang Y-C, Liu C, et al. PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis. Nat Cell Biol. 2020;22(10):1264–1275.
   PubMed Web of Science ®Google Scholar
• Wang M, Ma X, Zhou K, Mao H, Liu J, Xiong X, Zhao X, Narva S, Tanaka Y, Wu Y, et al. Discovery of pyrrole-imidazole polyamides as pd-l1 expression inhibitors and their anticancer activity via immune and nonimmune pathways. J Med Chem. 2021;64(9):6021–6036.
   PubMed Web of Science ®Google Scholar
• Zhang D, Reyes RM, Osta E, Kari S, Gupta HB, Padron AS, Kornepati AVR, Kancharla A, Sun X, Deng Y, et al. Bladder cancer cell-intrinsic PD-L1 signals promote mTOR and autophagy activation that can be inhibited to improve cytotoxic chemotherapy. Cancer Med. 2021;10(6):2137–2152.
   PubMed Web of Science ®Google Scholar
• Lu Y, Zhong W, Liu Y, Chen W, Zhang J, Zeng Z, Huang H, Qiao Y, Wan X, Meng X, et al. Anti-PD-L1 antibody alleviates pulmonary fibrosis by inducing autophagy via inhibition of the PI3K/Akt/mTOR pathway. Int Immunopharmacol. 2022;104:108504.
   PubMed Web of Science ®Google Scholar
• Yu J, Qin B, Moyer AM, Nowsheen S, Tu X, Dong H, Boughey JC, Goetz MP, Weinshilboum R, Lou Z, et al. Regulation of sister chromatid cohesion by nuclear PD-L1. Cell Res. 2020;30(7):590–601.
   PubMed Web of Science ®Google Scholar
• Almozyan S, Colak D, Mansour F, Alaiya A, Al-Harazi O, Qattan A, Al-Mohanna F, Al-Alwan M, Ghebeh H. PD-L1 promotes OCT4 and Nanog expression in breast cancer stem cells by sustaining PI3K/AKT pathway activation. Int J Cancer. 2017;141(7):1402–1412.
   PubMed Web of Science ®Google Scholar
• Chen C, Li S, Xue J, Qi M, Liu X, Huang Y, Hu J, Dong H, Ling K. PD-L1 tumor-intrinsic signaling and its therapeutic implication in triple-negative breast cancer. JCI Insight. 2021;6(8):e131458.
   Web of Science ®Google Scholar
• Clark CA, Gupta HB, Sareddy G, Pandeswara S, Lao S, Yuan B, Drerup JM, Padron A, Conejo-Garcia J, Murthy K, et al. Tumor-intrinsic pd-l1 signals regulate cell growth, pathogenesis, and autophagy in ovarian cancer and melanoma. Cancer Res. 2016;76(23):6964–6974.
   PubMed Web of Science ®Google Scholar
• Dong P, Xiong Y, Yue J, Hanley SJB, Watari H. Tumor-intrinsic PD-L1 signaling in cancer initiation, development and treatment: beyond immune evasion. Front Oncol. 2018;8:386.
   PubMed Web of Science ®Google Scholar
• Hudson K, Cross N, Jordan-Mahy N, Leyland R. The extrinsic and intrinsic roles of PD-L1 and its receptor PD-1: implications for immunotherapy treatment. Front Immunol. 2020;11:568931.
   PubMed Web of Science ®Google Scholar
• Cheng B, Xiao Y, Xue M, Cao H, Chen J. Recent advances in the development of PD-L1 modulators: degraders, downregulators, and covalent inhibitors. J Med Chem. 2020;63(24):15389–15398.
   PubMed Web of Science ®Google Scholar
• Cotton AD, Nguyen DP, Gramespacher JA, Seiple IB, Wells JA. Development of antibody-based PROTACs for the degradation of the cell-surface immune checkpoint protein PD-L1. J Am Chem Soc. 2021;143(2):593–598.
   PubMed Web of Science ®Google Scholar
• Liu R, Chen Y, Liu G, Li C, Song Y, Cao Z, Li W, Hu J, Lu C, Liu Y, et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers. Cell Death Dis. 2020;11(9):797.
   PubMed Web of Science ®Google Scholar