Therapeutic Potential of SHCBP1 Inhibitor AZD5582 in Pancreatic Cancer Treatment

Overview

Journal Cancer Sci

Specialty Oncology

Date 2023 Dec 28

PMID 38151993

Authors

Zhijian Ma

Qianlin Gu

Yiwei Dai

Qiaoyan Wang

Wengui Shi

Zuoyi Jiao

Affiliations

Soon will be listed here.

Abstract

Pancreatic cancer (PC) is a highly aggressive and deadly malignancy with limited treatment options and poor prognosis. Identifying new therapeutic targets and developing effective strategies for PC treatment is of utmost importance. Here, we revealed that SHCBP1 is significantly overexpressed in PC and negatively correlated with patient prognosis. Knockout of SHCBP1 inhibits the proliferation and migration of PC cells in vitro, and suppresses the tumor growth in vivo. In addition, we identified AZD5582 as a novel inhibitor of SHCBP1, which efficiently restrains the growth of PC in cell lines, organoids, and patient-derived xenografts. Mechanistically, we found that AZD5582 induced the apoptosis of PC cells by inhibiting the activity of PI3K/AKT signaling and preventing the degradation of TP53. Collectively, our study highlights SHCBP1 as a potential therapeutic target and its inhibitor AZD5582 as a viable agent for PC treatment strategies.

Citing Articles

Cancer cell-extrinsic STING shapes immune-active microenvironment and predicts clinical outcome in gastric cancer.

Wei Y, Ren Q, Hu P, Zou Y, Yao W, Qiu H Clin Transl Oncol. 2024; .

PMID: 39412634 DOI: 10.1007/s12094-024-03726-8.

Therapeutic potential of SHCBP1 inhibitor AZD5582 in pancreatic cancer treatment.

Ma Z, Gu Q, Dai Y, Wang Q, Shi W, Jiao Z Cancer Sci. 2023; 115(3):820-835.

PMID: 38151993 PMC: 10921007. DOI: 10.1111/cas.16059.

References

Park W, Chawla A, OReilly E . Pancreatic Cancer: A Review. JAMA. 2021; 326(9):851-862. PMC: 9363152. DOI: 10.1001/jama.2021.13027. View

Rathore R, McCallum J, Varghese E, Florea A, Busselberg D . Overcoming chemotherapy drug resistance by targeting inhibitors of apoptosis proteins (IAPs). Apoptosis. 2017; 22(7):898-919. PMC: 5486846. DOI: 10.1007/s10495-017-1375-1. View

Onuora S . Targeting IAPs ameliorates MPO-AAV. Nat Rev Rheumatol. 2022; 19(1):3. DOI: 10.1038/s41584-022-00885-2. View

Liu L, Yang Y, Liu S, Tao T, Cai J, Wu J . EGF-induced nuclear localization of SHCBP1 activates β-catenin signaling and promotes cancer progression. Oncogene. 2018; 38(5):747-764. PMC: 6355651. DOI: 10.1038/s41388-018-0473-z. View

Ma Z, Gu Q, Dai Y, Wang Q, Shi W, Jiao Z . Therapeutic potential of SHCBP1 inhibitor AZD5582 in pancreatic cancer treatment. Cancer Sci. 2023; 115(3):820-835. PMC: 10921007. DOI: 10.1111/cas.16059. View

Mizrahi J, Surana R, Valle J, Shroff R . Pancreatic cancer. Lancet. 2020; 395(10242):2008-2020. DOI: 10.1016/S0140-6736(20)30974-0. View

Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O . Highly accurate protein structure prediction with AlphaFold. Nature. 2021; 596(7873):583-589. PMC: 8371605. DOI: 10.1038/s41586-021-03819-2. View

Tempero M, Malafa M, Al-Hawary M, Behrman S, Benson A, Cardin D . Pancreatic Adenocarcinoma, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021; 19(4):439-457. DOI: 10.6004/jnccn.2021.0017. View

Shi W, Zhang G, Ma Z, Li L, Liu M, Qin L . Hyperactivation of HER2-SHCBP1-PLK1 axis promotes tumor cell mitosis and impairs trastuzumab sensitivity to gastric cancer. Nat Commun. 2021; 12(1):2812. PMC: 8121856. DOI: 10.1038/s41467-021-23053-8. View

10.

Read R, Baker E, Bond C, Garman E, van Raaij M . AlphaFold and the future of structural biology. IUCrJ. 2023; 10(Pt 4):377-379. PMC: 10324484. DOI: 10.1107/S2052252523004943. View

11.

Wang F, Li Y, Zhang Z, Wang J, Wang J . SHCBP1 regulates apoptosis in lung cancer cells through phosphatase and tensin homolog. Oncol Lett. 2019; 18(2):1888-1894. PMC: 6614682. DOI: 10.3892/ol.2019.10520. View

12.

Neoptolemos J, Kleeff J, Michl P, Costello E, Greenhalf W, Palmer D . Therapeutic developments in pancreatic cancer: current and future perspectives. Nat Rev Gastroenterol Hepatol. 2018; 15(6):333-348. DOI: 10.1038/s41575-018-0005-x. View

13.

Feng W, Li H, Xu K, Chen Y, Pan L, Mei Y . SHCBP1 is over-expressed in breast cancer and is important in the proliferation and apoptosis of the human malignant breast cancer cell line. Gene. 2016; 587(1):91-7. DOI: 10.1016/j.gene.2016.04.046. View

14.

Wright K, Miller B, El-Meanawy S, Tsaih S, Banerjee A, Geurts A . The p52 isoform of SHC1 is a key driver of breast cancer initiation. Breast Cancer Res. 2019; 21(1):74. PMC: 6570928. DOI: 10.1186/s13058-019-1155-7. View

15.

Zheng Y, Zhang C, Croucher D, Soliman M, St-Denis N, Pasculescu A . Temporal regulation of EGF signalling networks by the scaffold protein Shc1. Nature. 2013; 499(7457):166-71. PMC: 4931914. DOI: 10.1038/nature12308. View

16.

Hou H, Su K, Huang C, Yuan Q, Li S, Sun J . TRAIL-Armed ER Nanosomes Induce Drastically Enhanced Apoptosis in Resistant Tumor in Combination with the Antagonist of IAPs (AZD5582). Adv Healthc Mater. 2021; 10(11):e2100030. DOI: 10.1002/adhm.202100030. View

17.

Kumar S, Fairmichael C, Longley D, Turkington R . The Multiple Roles of the IAP Super-family in cancer. Pharmacol Ther. 2020; 214:107610. DOI: 10.1016/j.pharmthera.2020.107610. View

18.

Yang C, Hu J, Zhan Q, Wang Z, Li G, Pan J . SHCBP1 interacting with EOGT enhances O-GlcNAcylation of NOTCH1 and promotes the development of pancreatic cancer. Genomics. 2021; 113(2):827-842. DOI: 10.1016/j.ygeno.2021.01.010. View

19.

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z . GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017; 45(W1):W98-W102. PMC: 5570223. DOI: 10.1093/nar/gkx247. View

20.

Schmandt R, Liu S, McGlade C . Cloning and characterization of mPAL, a novel Shc SH2 domain-binding protein expressed in proliferating cells. Oncogene. 1999; 18(10):1867-79. DOI: 10.1038/sj.onc.1202507. View