Deciphering the impact of STAT3 activation mediated by PTPRT promoter hypermethylation as biomarker of response to paclitaxel-plus-cetuximab in patients with recurrent or metastatic squamous cell carcinoma of the head and neck.
PTPRT
STAT3
cetuximab
methylation
paclitaxel
squamous cell carcinoma of the head and neck
Journal
Head & neck
ISSN: 1097-0347
Titre abrégé: Head Neck
Pays: United States
ID NLM: 8902541
Informations de publication
Date de publication:
27 Jul 2024
27 Jul 2024
Historique:
revised:
10
06
2024
received:
08
04
2024
accepted:
12
07
2024
medline:
29
7
2024
pubmed:
29
7
2024
entrez:
29
7
2024
Statut:
aheadofprint
Résumé
Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor prognosis. It is known that the activation of STAT3 signaling pathways promotes the development and progression of this neoplasia and it has been described the role of PTPRT as a negative regulator of STAT3. Then, we have evaluated the impact of them as biomarkers of outcome in a series of patients with recurrent and/or metastatic SCCHN treated with weekly paclitaxel-plus-cetuximab (ERBITAX) regimen. Between 2008 and 2017, 52 patients with recurrent/metastatic SCCHN were treated with ERBITAX at our center, 34 of whom had available tumor samples. Phosphorylated STAT3 (pSTAT3) protein expression was analyzed by immunohistochemistry, STAT3 mRNA expression by qPCR, and PTPRT promoter methylation by methylation-specific PCR. Molecular results were correlated with response rate (RR), progression-free survival (PFS), and overall survival (OS). pSTAT3 overexpression was detected in 67% and PTPRT promoter hypermethylation in 41% of tumor samples. PTPRT promoter hypermethylation showed a trend towards an association with lower RR (21% vs. 60%; p = 0.06). A lower RR was also observed in patients with pSTAT3 overexpression (36% vs. 54%) and in those with high STAT3 mRNA levels (43% vs. 64%), but these differences did not reach statistical significance. PTPRT promoter hypermethylation correlated with pSTAT3 overexpression (p = 0.009) but not with STAT3 mRNA overexpression. OS and PFS was shorter in patients with activated STAT3, but the difference did not reach statistical significance. Although this was a relatively small retrospective study, it provides preliminary indications of the potential role of the STAT3 pathway on outcome in SCCHN and confirms that PTPRT acts as a negative regulator of STAT3. Our findings warrant investigation in a larger patient cohort to determine if inactivating this pathway through specific targeted treatments could improve outcomes in recurrent/metastatic SCCHN patients.
Sections du résumé
BACKGROUND
BACKGROUND
Squamous cell carcinoma of the head and neck (SCCHN) is an aggressive disease with poor prognosis. It is known that the activation of STAT3 signaling pathways promotes the development and progression of this neoplasia and it has been described the role of PTPRT as a negative regulator of STAT3. Then, we have evaluated the impact of them as biomarkers of outcome in a series of patients with recurrent and/or metastatic SCCHN treated with weekly paclitaxel-plus-cetuximab (ERBITAX) regimen.
PATIENTS AND METHODS
METHODS
Between 2008 and 2017, 52 patients with recurrent/metastatic SCCHN were treated with ERBITAX at our center, 34 of whom had available tumor samples. Phosphorylated STAT3 (pSTAT3) protein expression was analyzed by immunohistochemistry, STAT3 mRNA expression by qPCR, and PTPRT promoter methylation by methylation-specific PCR. Molecular results were correlated with response rate (RR), progression-free survival (PFS), and overall survival (OS).
RESULTS
RESULTS
pSTAT3 overexpression was detected in 67% and PTPRT promoter hypermethylation in 41% of tumor samples. PTPRT promoter hypermethylation showed a trend towards an association with lower RR (21% vs. 60%; p = 0.06). A lower RR was also observed in patients with pSTAT3 overexpression (36% vs. 54%) and in those with high STAT3 mRNA levels (43% vs. 64%), but these differences did not reach statistical significance. PTPRT promoter hypermethylation correlated with pSTAT3 overexpression (p = 0.009) but not with STAT3 mRNA overexpression. OS and PFS was shorter in patients with activated STAT3, but the difference did not reach statistical significance.
CONCLUSIONS
CONCLUSIONS
Although this was a relatively small retrospective study, it provides preliminary indications of the potential role of the STAT3 pathway on outcome in SCCHN and confirms that PTPRT acts as a negative regulator of STAT3. Our findings warrant investigation in a larger patient cohort to determine if inactivating this pathway through specific targeted treatments could improve outcomes in recurrent/metastatic SCCHN patients.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
© 2024 Wiley Periodicals LLC.
Références
Hitt R, Irigoyen A, Cortes‐Funes H, Grau JJ, Garcia‐Saenz JA, Cruz‐Hernandez JJ. Spanish Head and Neck Cancer Cooperative Group (TTCC). Phase II study of the combination of cetuximab and weekly paclitaxel in the first‐line treatment of patients with recurrent and/or metastatic squamous cell carcinoma of head and neck. Ann Oncol. 2012;23(4):1016‐1022.
Rubió‐Casadevall J, Cirauqui Cirauqui B, Martinez Trufero J, Plana Serrahima M, García Castaño A, Carral MA. TTCC‐2019‐02: real‐world evidence of first‐line cetuximab plus paclitaxel in recurrent or metastatic squamous cell carcinoma of the head and neck. Front Oncol. 2023;13:1226939.
Akervall J, Bockmuhl U, Petersen I, Yang K, Carey TE, Kurnit DM. The gene ratios c‐MYC: cyclin‐dependent kinase (CDK) N2A and CCND1:CDKN2A correlate with poor prognosis in squamous cell carcinoma of the head and neck. Clin Cancer Res. 2003;9(5):1750‐1755.
Al Zaid Siddiquee K, Turkson J. STAT3 as a target for inducing apoptosis in sòlid and hematological tumors. Cell Res. 2008;18(2):254‐267.
Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head and neck cancer. J Clin Oncol. 2006;24(17):2666‐2672.
Johnson DE, O'Keefe RA, Grandis JR. Targeting the IL‐6/JAK/STAT3 signalling axis in cancer. Nat Rev Clin Oncol. 2018;15(4):234‐248.
Xi S, Zhang Q, Dyer KF, et al. Src kinases mediate STAT growth pathways in squamous cell carcinoma of the head and neck. J Biol Chem. 2003;278(34):31574‐31583.
Yu H, Jove R. The STATs of cancer‐new molecular targets come of age. Nat Rev Cancer. 2004;4(2):97‐105.
Gao P, Niu N, Wei T, et al. The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis. Oncotarget. 2017;8(40):69139‐69161.
Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7(1):41‐51.
Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5(9):744‐749.
Thiery JP. Epithelial‐mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2(6):442‐454.
Masuda M, Wakasaki T, Suzui M, Toh S, Joe AK, Weinstein IB. Stat3 orchestrates tumor development and progression: the Achilles' heel of head and neck cancers? Curr Cancer Drug Targets. 2010;10(1):117‐126.
Peyser ND, Du Y, Li H, et al. Loss‐of‐function PTPRD mutations lead to increased STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer. PLoS One. 2015;10(8):e0135750.
Peyser ND, Freilino M, Wang L, et al. Frequent promoter hypermethylation of PTPRT increases STAT3 activation and sensitivity to STAT3 inhibition in head and neck cancer. Oncogene. 2016;35(9):1163‐1169.
Walker SR, Chaudhury M, Nelson EA, Frank DA. Microtubule‐targeted chemotherapeutic agents inhibit signal transducer and activator of transcription 3 (STAT3) signaling. Mol Pharmacol. 2010;78(5):903‐908.
Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous‐cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567‐578.
Ang KK, Berkey BA, Tu X, et al. Impact of epidermal growth factor receptor expression on survival and pattern of relapse in patients with advanced head and neck carcinoma. Cancer Res. 2002;62(24):7350‐7356.
Geiger JL, Grandis JR, Bauman JE. The STAT3 pathway as a therapeutic target in head and neck cancer: barriers and innovations. Oral Oncol. 2016;56:84‐92.
Kijima T, Niwa H, Steinman RA, et al. STAT3 activation abrogates growth factor dependence and contributes to head and neck squamous cell carcinoma tumor growth in vivo. Cell Growth Differ. 2002;13(8):355‐6221.
Lo HW, Cao X, Zhu H, Ali‐Osman F. Constitutively activated STAT3 frequently coexpresses with epidermal growth factor receptor in high‐grade gliomas and targeting STAT3 sensitizes them to Iressa and alkylators. Clin Cancer Res. 2008;14(19):6042‐6054.
Uozumi S, Enokida T, Suzuki S, et al. Predictive value of cetuximab‐induced skin toxicity in recurrent or metastatic squamous cell carcinoma of the head and neck. Front Oncol. 2018;13(8):616.
Human Protein Atlas. https://www.proteinatlas.org/ENSG00000168610‐STAT3/cell. Accessed August 31, 2023
The Cancer Genome Atlas (TCGA). https://www.genome.gov/Funded-Programs-Projects/Cancer-Genome-Atlas. Accessed August 31, 2023
Peyser ND, Pendleton K, Gooding WE, Lui VW, Johnson DE, Grandis JR. Genomic and transcriptomic alterations associated with STAT3 activation in head and neck cancer. PLoS One. 2016;11(11):e0166185.
Peyser ND, Wang L, Zeng Y, Acquafondata M, Freilino M, Li H. STAT3 as a chemoprevention target in carcinogen‐induced head and neck squamous cell carcinoma. Cancer Prev Res (Phila). 2016;9(8):657‐663.
Wu P, Wu D, Zhao L, et al. Prognostic role of STAT3 in solid tumors: a systematic review and meta‐analysis. Oncotarget. 2016;7(15):19863‐19883.
STAT3 signal transducer and activator of transcription 3 [ Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/6774?report=expression. Accessed August 31, 2023
Jones PA, Ohtani H, Chakravarthy A, De Carvalho DD. Epigenetic therapy in immune oncology. Nat Rev Cancer. 2019;19(3):151‐161.
Udali S, De Santis D, Ruzzenente A, et al. DNA 251 methylation and hydroxymethylation in primary colon cancer and synchronous hepatic metastasis. Front Genet. 2018;9(8):22931.
Martínez‐Cardús A, Moran S, Musulen E, et al. Epigenetic homogeneity within colorectal tumors predicts shorter relapse‐free and overall survival times for patients with locoregional cancer. Gastroenterology. 2016;151(5):961‐972.
Duruisseaux M, Martínez‐Cardús A, Calleja‐Cervantes ME, et al. Epigenetic prediction of response to anti‐PD‐1 treatment in non‐small‐cell lung cancer: a multicentre, retrospective analysis. Lancet. Respir Med. 2018;6(10):771‐781.
Cohen EEW, Harrington KJ, Hong DS, et al. A phase Ib/II study (SCORES) of durvalumab (D) plus danvatirsen (DAN; AZD9150) or 241 AZD5069 (CX2i) in advanced solid malignancies and recurrent/metastatic head and neck squamous cell carcinoma (RM‐HNSCC): updated results. Ann Oncol. 2018;29(8):viii372.
Lee H, Jeong AJ, Ye SK. Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep. 2019;52(7):415‐423.