Targeting Ataxia Telangiectasia-Mutated and Rad3-Related for Anaplastic Thyroid Cancer

Overview

Journal Cancers (Basel)

Publisher MDPI

Specialty Oncology

Date 2025 Feb 13

PMID 39941729

Authors

Shu-Fu Lin

Chuen Hsueh

Wei-Yi Chen

Ting-Chao Chou

Richard J Wong

Affiliations

Soon will be listed here.

Abstract

Background: Anaplastic thyroid cancer (ATC) is one of the most aggressive human malignancies and has a poor prognosis. Ataxia telangiectasia mutated and Rad3 related (ATR) is a key regulator for the DNA damage response and a potential target to treat cancer.

Methods: We assessed the efficacy of BAY 1895344, an ATR inhibitor, in three ATC cell lines.

Results: BAY 1895344 caused dose-response cytotoxicity in three ATC cell lines. BAY 1895344 induced S-phase and G2-phase arrest, activated caspase-3 activity and induced apoptosis in ATC cells. BAY 1895344 meaningfully retarded the tumor growth of an ATC xenograft model. BAY 1895344 therapy, combined with dabrafenib and trametinib, had synergism in vitro and revealed robust tumor growth suppression in vivo in two xenograft models of ATC harboring mutant . Furthermore, the combination of BAY 1895344 with lenvatinib was more effective than either agent alone in a xenograft model of ATC.

Conclusions: These results reveal that BAY 1895344 has potential in treating ATC.

References

Lecona E, Fernandez-Capetillo O . Replication stress and cancer: it takes two to tango. Exp Cell Res. 2014; 329(1):26-34. PMC: 4878650. DOI: 10.1016/j.yexcr.2014.09.019. View

Carneiro B, El-Deiry W . Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020; 17(7):395-417. PMC: 8211386. DOI: 10.1038/s41571-020-0341-y. View

Ito T, Seyama T, Hayashi Y, Hayashi T, Dohi K, Mizuno T . Establishment of 2 human thyroid-carcinoma cell-lines (8305c, 8505c) bearing p53 gene-mutations. Int J Oncol. 2011; 4(3):583-6. DOI: 10.3892/ijo.4.3.583. View

Couch F, Bansbach C, Driscoll R, Luzwick J, Glick G, Betous R . ATR phosphorylates SMARCAL1 to prevent replication fork collapse. Genes Dev. 2013; 27(14):1610-23. PMC: 3731549. DOI: 10.1101/gad.214080.113. View

Buisson R, Niraj J, Rodrigue A, Ho C, Kreuzer J, Foo T . Coupling of Homologous Recombination and the Checkpoint by ATR. Mol Cell. 2017; 65(2):336-346. PMC: 5496772. DOI: 10.1016/j.molcel.2016.12.007. View

Lin S, Huang Y, Lin J, Chou T, Hsueh C, Wong R . Utility of a PI3K/mTOR inhibitor (NVP-BEZ235) for thyroid cancer therapy. PLoS One. 2012; 7(10):e46726. PMC: 3471922. DOI: 10.1371/journal.pone.0046726. View

Gamper A, Rofougaran R, Watkins S, Greenberger J, Beumer J, Bakkenist C . ATR kinase activation in G1 phase facilitates the repair of ionizing radiation-induced DNA damage. Nucleic Acids Res. 2013; 41(22):10334-44. PMC: 3905881. DOI: 10.1093/nar/gkt833. View

Schweppe R, Klopper J, Korch C, Pugazhenthi U, Benezra M, Knauf J . Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. J Clin Endocrinol Metab. 2008; 93(11):4331-41. PMC: 2582569. DOI: 10.1210/jc.2008-1102. View

Lin S, Lee Y, Wu M, Lu Y, Yeh C, Chen W . Therapeutic inhibition of ATR in differentiated thyroid cancer. Endocr Relat Cancer. 2023; 30(12). PMC: 11271744. DOI: 10.1530/ERC-23-0142. View

10.

Subbiah V, Kreitman R, Wainberg Z, Cho J, Schellens J, Soria J . Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Ann Oncol. 2022; 33(4):406-415. PMC: 9338780. DOI: 10.1016/j.annonc.2021.12.014. View

11.

Groelly F, Fawkes M, Dagg R, Blackford A, Tarsounas M . Targeting DNA damage response pathways in cancer. Nat Rev Cancer. 2022; 23(2):78-94. DOI: 10.1038/s41568-022-00535-5. View

12.

Pozdeyev N, Gay L, Sokol E, Hartmaier R, Deaver K, Davis S . Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers. Clin Cancer Res. 2018; 24(13):3059-3068. PMC: 6030480. DOI: 10.1158/1078-0432.CCR-18-0373. View

13.

Mei L, Zhang J, He K, Zhang J . Ataxia telangiectasia and Rad3-related inhibitors and cancer therapy: where we stand. J Hematol Oncol. 2019; 12(1):43. PMC: 6482552. DOI: 10.1186/s13045-019-0733-6. View

14.

Cimprich K, Cortez D . ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol. 2008; 9(8):616-27. PMC: 2663384. DOI: 10.1038/nrm2450. View

15.

Min A, Im S, Jang H, Kim S, Lee M, Kim D . AZD6738, A Novel Oral Inhibitor of ATR, Induces Synthetic Lethality with ATM Deficiency in Gastric Cancer Cells. Mol Cancer Ther. 2017; 16(4):566-577. DOI: 10.1158/1535-7163.MCT-16-0378. View

16.

Lin S, Yu Z, Riedl C, Woo Y, Zhang Q, Yu Y . Treatment of anaplastic thyroid carcinoma in vitro with a mutant vaccinia virus. Surgery. 2007; 142(6):976-83. DOI: 10.1016/j.surg.2007.09.017. View

17.

Trenner A, Sartori A . Harnessing DNA Double-Strand Break Repair for Cancer Treatment. Front Oncol. 2020; 9:1388. PMC: 6921965. DOI: 10.3389/fonc.2019.01388. View

18.

. AACR Project GENIE: Powering Precision Medicine through an International Consortium. Cancer Discov. 2017; 7(8):818-831. PMC: 5611790. DOI: 10.1158/2159-8290.CD-17-0151. View

19.

Blackford A, Jackson S . ATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response. Mol Cell. 2017; 66(6):801-817. DOI: 10.1016/j.molcel.2017.05.015. View

20.

Sugitani I, Miyauchi A, Sugino K, Okamoto T, Yoshida A, Suzuki S . Prognostic factors and treatment outcomes for anaplastic thyroid carcinoma: ATC Research Consortium of Japan cohort study of 677 patients. World J Surg. 2012; 36(6):1247-54. DOI: 10.1007/s00268-012-1437-z. View