Cancer Research and Treatment

Original Articles

Genitourinary cancer

PD-L1 Upregulation by the mTOR Pathway in VEGFR-TKI–Resistant Metastatic Clear Cell Renal Cell Carcinoma: Se Un Jeong, Hee Sang Hwang, Ja-Min Park, Sun Young Yoon, Su-Jin Shin, Heounjeong Go, Jae-Lyun Lee, Gowun Jeong, Yong Mee Cho; Cancer Res Treat. 2023;55(1):231-244. Published online March 2, 2022; DOI: https://doi.org/10.4143/crt.2021.1526

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Purpose
Tyrosine kinase inhibitors (TKI) targeting vascular endothelial growth factor receptor (VEGFR) signaling pathways have been used for metastatic clear cell renal cell carcinoma (mCCRCC), but resistance to the drug develops in most patients. We aimed to explore the underlying mechanism of the TKI resistance with regard to programmed death-ligand 1 (PD-L1) and to investigate signaling pathway associated with the resistant mechanism.
Materials and Methods
To determine the mechanism of resistance, 10 mCCRCC patients from whom tumor tissues were harvested at both the pretreatment and the TKI-resistant post-treatment period were included as the discovery cohort, and their global gene expression profiles were compared. A TKI-resistant renal cancer cell line was established by long-term treatment with sunitinib.
Results
Among differentially expressed genes in the discovery cohort, increased PD-L1 expression in post-treatment tissues was noted in four patients. Pathway analysis showed that PD-L1 expression was positively correlated with the mammalian target of rapamycin (mTOR) signaling pathway. The TKI-resistant renal cancer cells showed increased expression of PD-L1 and mTOR signaling proteins and demonstrated aggressive tumoral behaviour. Treatment with mTOR inhibitors down-regulated PD-L1 expression and suppressed aggressive tumoral behaviour, which was reversed with stimulation of the mTOR pathway.
Conclusion
These results showed that PD-L1 expression may be increased in a subset of VEGFR-TKI–resistant mCCRCC patients via the mTOR pathway.

Citations

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IFITM3-mediated activation of TRAF6/MAPK/AP-1 pathways induces acquired TKI resistance in clear cell renal cell carcinoma
Se Un Jeong, Ja-Min Park, Sun Young Yoon, Hee Sang Hwang, Heounjeong Go, Dong-Myung Shin, Hyein Ju, Chang Ohk Sung, Jae-Lyun Lee, Gowun Jeong, Yong Mee Cho
Investigative and Clinical Urology.2024; 65(1): 84. CrossRef
Targeting apoptosis in clear cell renal cell carcinoma
Adam Kowalewski, Jędrzej Borowczak, Mateusz Maniewski, Karol Gostomczyk, Dariusz Grzanka, Łukasz Szylberg
Biomedicine & Pharmacotherapy.2024; 175: 116805. CrossRef
Therapeutic advances of targeting receptor tyrosine kinases in cancer
Ciprian Tomuleasa, Adrian-Bogdan Tigu, Raluca Munteanu, Cristian-Silviu Moldovan, David Kegyes, Anca Onaciu, Diana Gulei, Gabriel Ghiaur, Hermann Einsele, Carlo M. Croce
Signal Transduction and Targeted Therapy.2024;[Epub] CrossRef
Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics
Yunxia Wang, Xiaolin Liu, Luyao Gong, Weihong Ding, Wenjing Hao, Yeheng Peng, Jun Zhang, Weimin Cai, Yuan Gao
British Journal of Pharmacology.2023; 180(23): 2937. CrossRef
Prior Anti-Angiogenic TKI-Based Treatment as Potential Predisposing Factor to Nivolumab-Mediated Recurrent Thyroid Disorder Adverse Events in mRCC Patients: A Case Series
Luigi Liguori, Angelo Luciano, Giovanna Polcaro, Alessandro Ottaiano, Marco Cascella, Francesco Perri, Stefano Pepe, Francesco Sabbatino
Biomedicines.2023; 11(11): 2974. CrossRef

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Lymphoma

Prognostic Impact of Age at the Time of Diagnosis in Korean Patients with Diffuse Large B-cell Lymphoma in the Rituximab Era: A Single Institution Study: Hee Sang Hwang, Meejeong Kim, Chan-Sik Park, Dok Hyun Yoon, Cheolwon Suh, Jooryung Huh, Heounjeong Go; Cancer Res Treat. 2021;53(1):270-278. Published online September 15, 2020; DOI: https://doi.org/10.4143/crt.2020.626

Abstract PDF Supplementary Material PubReader ePub

Purpose
In contrast to the Western diffuse large B-cell lymphoma (DLBCL), prognostic impact of age in a Korean population with DLBCL has not been fully evaluated.
Materials and Methods
Six hundred and eight DLBCL patients treated with rituximab-containing chemotherapeutic regimens from January 2002 to March 2012 in Asan Medical Center were enrolled. Survival models using the restricted cubic spine−transformed age variable were constructed to evaluate non-linear relationships between age and survival outcome. Finally, age was categorized according to the conventional international prognostic index (IPI), National Comprehensive Cancer Network (NCCN)-IPI, and Grupo Español de Linfomas/Trasplante Autólogo de Médula Ósea (GELTAMO)-IPI schemes and the prognostic implications were evaluated.
Results
The relative hazard did not change significantly during the first to fifth decades, but began to increase exponentially in patients aged over 62 years. This pattern or relationship was also retained in a multivariate model fitted to the age-adjusted IPI and relative dose intensity. Multivariate survival analysis revealed that age > 75 years, but not age > 60 years, was associated independently with poor overall and progression-free survival when the relative dose intensity and age-adjusted IPI were taken into account.
Conclusion
The outcome of DLBCL in Korean populations may deteriorate rapidly as age exceeds 62 years. Therefore, a consensus cutoff value for age in Korean DLBCL patients should be determined to better predict prognosis.

Citations

Citations to this article as recorded by

Two distinct age-prognosis patterns in patients with esophageal cancer undergoing surgical and radiotherapy treatments: a combined analysis of 3JECROG and SEER databases
Chen Li, Xiao Chang, Qifeng Wang, Qingsong Pang, Zefen Xiao, Wencheng Zhang, Zhiyong Yuan
Therapeutic Advances in Medical Oncology.2024;[Epub] CrossRef
SOHO State of the Art Updates and Next Questions | Diffuse Large B-Cell Lymphoma in Older Adults: A Comprehensive Review
Varun Iyengar, Paul Hamlin, Pallawi Torka
Clinical Lymphoma Myeloma and Leukemia.2024;[Epub] CrossRef
Impact of R-CHOP dose intensity on survival outcomes in diffuse large B-cell lymphoma: a systematic review
Edward J. Bataillard, Chan Yoon Cheah, Matthew J. Maurer, Arushi Khurana, Toby A. Eyre, Tarec Christoffer El-Galaly
Blood Advances.2021; 5(9): 2426. CrossRef

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