QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis

Zhao, Tangliang; Zhou, Yanmin; Wang, Qingyun; Yi, Xiaoming; Ge, Silun; He, Haowei; Xue, Song; Du, Bowen; Ge, Jingping; Dong, Jie; Qu, Le; Wang, Linhui; Zhou, Wenquan

doi:10.3892/ijo.2021.5228

Cited by 7 publications

(6 citation statements)

References 42 publications

(70 reference statements)

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“…Overexpression of MTDH is noted in aggressive BC subsets, such as triplenegative BC and HER2-overexpressed tumors (37). QPCT, a secreted protein implicated in the biosynthesis of pyroglutamyl peptides, is found to contribute to angiogenesis (38). Our preceding experiment suggested that MTDH and QPCT were intensively expressed in local advanced breast tumors and positively correlated with poor disease-free survival.…”

Section: Discussionmentioning

confidence: 95%

Pegylated Liposomal Doxorubicin, Docetaxel, and Trastuzumab as Neoadjuvant Treatment for HER2-Positive Breast Cancer Patients: A Phase II and Biomarker Study

Wang

et al. 2022

Front. Oncol.

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BackgroundCombined neoadjuvant chemotherapy with trastuzumab and pertuzumab is the standard regimen for human epidermal growth receptor 2 (HER2)-positive breast cancer (BC). However, pertuzumab is not available because it is not on the market or covered by medicare in some regions or poor economy. Anthracyclines and taxanes are cornerstones in BC chemotherapy, and their combination contributes to satisfactory efficiency in neoadjuvant settings. Nonetheless, concomitant administration of trastuzumab and an anthracycline is generally avoided clinically due to cardiotoxicity. Pegylated liposomal doxorubicin (PLD) is less cardiotoxic compared with traditional anthracyclines. Here, we conducted this prospective study to evaluate the efficacy, safety, and potential biomarkers for PLD plus trastuzumab and docetaxel as neoadjuvant treatment in HER2-positive BC.Patients and MethodsPatients with stage II or III HER2-positive BC were recruited in this multicenter, open-label, single-arm, phase II study. Eligible patients were given 6 cycles of PLD plus docetaxel and trastuzumab. Primary endpoint was total pathological complete response (tpCR, ypT0/is ypN0). Secondary endpoints were breast pathological complete response (bpCR, ypT0/is), objective response rate (ORR), operation rate, breast-conserving surgery rate, and safety. Metadherin (MTDH), glutaminyl-peptide cyclotransferase (QPCT), topoisomerase II alpha (TOP2A), programmed death ligand 1 (PD-L1), and tumor-infiltrating lymphocytes (TILs) were evaluated in BC tissues pre-neoadjuvant for potential biomarkers.ResultsBetween March 2019 and February 2021, 54 patients were enrolled, 50 were included in the analysis, and 35 (70.0%) completed 6 cycles of neoadjuvant treatment. Forty-nine (98.0%) patients underwent surgery with a breast-conserving rate of 44.0%. The tpCR rate, bpCR rate, and ORR were 48.0% (95% CI, 33.7%–62.6%), 60.0% (95% CI, 45.2%–73.6%), and 84.0% (95% CI, 70.9%–92.8%), respectively. tpCR was associated with MTDH (p = 0.002) and QPCT (p = 0.036) expression but not with TOP2A (p = 0.75), PD-L1 (p = 0.155), or TILs (p = 0.76). Patients with HR-negative status were more likely to achieve bpCR compared with those with HR-positive status (76.2% vs. 48.3%, p = 0.047). Grade ≥3 adverse events occurred in 38.0% of patients. Left ventricular ejection fraction decline by ≥10% was reported in 18.0% of patients, and no patient experienced congestive heart failure.ConclusionsPLD plus docetaxel and trastuzumab might be a potential neoadjuvant regimen for HER2-positive BC with a high tpCR rate and manageable tolerability. MTDH and QPCT are potential predictive markers for tpCR.

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Section: Discussionmentioning

confidence: 95%

Pegylated Liposomal Doxorubicin, Docetaxel, and Trastuzumab as Neoadjuvant Treatment for HER2-Positive Breast Cancer Patients: A Phase II and Biomarker Study

Wang

et al. 2022

Front. Oncol.

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“…The regulation function of QPCTL of monocyte infiltration under inflammatory conditions had been demonstrated a long time ago ( 37 ). In renal cell carcinoma, the high expression of QPCTL leads to sunitinib resistance by promoting angiogenesis ( 38 ). In chronic kidney disease, chronic treatment with QPCTL inhibitor PQ529 is a novel and effective approach for glomerulonephritis ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Deciphering the role of QPCTL in glioma progression and cancer immunotherapy

Liu

Sun

et al. 2023

Front. Immunol.

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BackgroundGlioma is the most lethal and most aggressive brain cancer, and currently there is no effective treatment. Cancer immunotherapy is an advanced therapy by manipulating immune cells to attack cancer cells and it has been studied a lot in glioma treatment. Targeting the immune checkpoint CD47 or blocking the CD47-SIRPα axis can effectively eliminate glioma cancer cells but also brings side effects such as anemia. Glutaminyl-peptide cyclotransferase-like protein (QPCTL) catalyzes the pyroglutamylation of CD47 and is crucial for the binding between CD47 and SIRPα. Further study found that loss of intracellular QPCTL limits chemokine function and reshapes myeloid infiltration to augment tumor immunity. However, the role of QPCTL in glioma and the relationship between its expression and clinical outcomes remains unclear. Deciphering the role of QPCTL in glioma will provide a promising therapy for glioma cancer immunotherapy.MethodsQPCTL expression in glioma tissues and normal adjacent tissues was primarily analyzed in The Cancer Genome Atlas (TCGA) database, and further validated in another independent cohort from the Gene Expression Omnibus (GEO) database, Chinese Glioma Genome Atlas (CGGA), and Human Protein Atlas (HPA). The relationships between QPCTL expression and clinicopathologic parameters and overall survival (OS) were assessed using multivariate methods and Kaplan-Meier survival curves. And the proteins network with which QPCTL interacted was built using the online STRING website. Meanwhile, we use Tumor Immune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA) databases to investigate the relationships between QPCTL expression and infiltrated immune cells and their corresponding gene marker sets. We analyzed the Differentially Expressed Genes (DEGs) including GO/KEGG and Gene Set Enrichment Analysis (GSEA) based on QPCTL-high and -low expression tumors.ResultsIn contrast to normal tissue, QPCTL expression was higher in glioma tumor tissue (p < 0.05). Higher QPCTL expression was closely associated with high-grade malignancy and advanced tumor stage. Univariate and multivariate analysis indicated the overall survival of glioma patients with higher QPCTL expression is shorter than those with lower QPCTL expression (p < 0.05). Glioma with QPCTL deficiency presented the paucity of infiltrated immune cells and their matching marker sets. Moreover, QPCTL is essential for glioma cell proliferation and tumor growth and is a positive correlation with glioma cell stemness.ConclusionHigh QPCTL expression predicts high grades of gliomas and poor prognosis with impaired infiltration of adaptive immune cells in the tumor microenvironment as well as higher cancer stemness. Moreover, targeting QPCTL will be a promising immunotherapy in glioma cancer treatment.

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“…Glutaminyl‐peptide cyclotransferase (QPCT) is closely related to sunitinib resistance through high‐throughput sequencing (Zhao et al, 2021). The expression of QPCT increased in the sunitinib‐nonresponsive renal cell carcinoma tissues and plasma, and renal cell carcinoma patients with a high QPCT expression have a poor response to sunitinib.…”

Section: Molecular Mechanisms Of Sunitinib Resistancementioning

confidence: 99%

Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics

Wang,

Liu,

Gong

et al. 2023

British J Pharmacology

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Sunitinib is the first‐line drug for renal cell carcinoma (RCC) treatment. However, patients who received sunitinib treatment will ultimately develop drug resistance after 6‐15 months, creating a huge obstacle to the current treatment of RCC. Therefore, it is urgent to clarify the mechanisms of sunitinib resistance and develop new strategies to overcome it. In this review, the mechanisms of sunitinib resistance in RCC have been summarized based on five topics: activation of bypass or alternative pathway, inadequate drug accumulation, tumor microenvironment, metabolic reprogramming and epigenetic regulation. Furthermore, present and potential biomarkers, as well as potential treatment strategies for overcoming sunitinib resistance in RCC are illustrated.

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QPCT regulation by CTCF leads to sunitinib resistance in renal cell carcinoma by promoting angiogenesis

Cited by 7 publications

References 42 publications

Pegylated Liposomal Doxorubicin, Docetaxel, and Trastuzumab as Neoadjuvant Treatment for HER2-Positive Breast Cancer Patients: A Phase II and Biomarker Study

Pegylated Liposomal Doxorubicin, Docetaxel, and Trastuzumab as Neoadjuvant Treatment for HER2-Positive Breast Cancer Patients: A Phase II and Biomarker Study

Deciphering the role of QPCTL in glioma progression and cancer immunotherapy

Mechanisms of sunitinib resistance in renal cell carcinoma and associated opportunities for therapeutics

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