Endothelial p130cas confers resistance to anti-angiogenesis therapy

Wen, Yunfei; Chelariu-Raicu, Anca; Umamaheswaran, Sujanitha; Nick, Alpa M.; Stur, Elaine; Hanjra, Pahul; Jiang, Dahai; Jennings, Nicholas B.; Chen, Xiuhui; Corvigno, Sara; Glassman, Deanna; López-Berestein, Gabriel; Liu, Jinsong; Hung, Mien‐Chie; Sood, Anil K.

doi:10.1016/j.celrep.2022.110301

Cited by 5 publications

(2 citation statements)

References 55 publications

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“…For instance, we observed upregulation of EZH2 in liver cancer samples with a mutation in the predicted distal enhancers of the EZH2 gene, which is known to promote hepatocellular carcinoma (HCC) progression and metastasis ( 43 , 44 ) and its inhibitors are currently being tested in clinical trials ( 45 ). Other examples of genes upregulated in the mutated samples include: (i) STOML2 (liver), which promotes colony formation, migration and invasion of HCC cells ( 46 ) and its downregulation leads to increased sensitivity to lenvatinib ( 47 ), (ii) PLAU (lung), which is a key component of the long-known oncogenic plasminogen activator system important in lung tumour progression, proliferation and metastasis ( 48 ), is being tested as a drug target ( 49 ), and is overexpressed in progressive lung cancer ( 50 ), (iii) CCND1 (lung), a druggable gene ( 51 ) known to promote lung cancer growth and metastasis ( 52 ), (iv) IER1 (colorectal cancer), the deficiency of which protects against colorectal cancer in mice ( 53 ), (v) IKBKB (colorectal cancer), which promotes carcinogenesis via activation of Wnt signalling and production of pro-inflammatory intestinal microenvironment ( 54 ), (vi) PARP2 (pancreas), an important therapeutic target ( 55 ), (vii) BCAR1 (p130Cas; in ovary) a well-known oncogene in ovarian cancer ( 56 ), which confers resistance to anti-angiogenesis therapy in ovarian tumours ( 57 ), (viii) PRKACA (breast), an anti-apoptotic oncogene mediating resistance to HER2-targeted breast-cancer therapy ( 58 ), (ix) CKS1B (breast), anti-apoptotic pro-invasive oncogene in breast cancer ( 59 ) and a drug resistance-inducing gene ( 60 ), and many others ( Supplementary Table S3 ).…”

Section: Discussionmentioning

confidence: 99%

Dr.Nod: computational framework for discovery of regulatory non-coding drivers in tissue-matched distal regulatory elements

Tomková

Tomek

Chow

et al. 2023

Nucleic Acids Research

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The discovery of cancer driver mutations is a fundamental goal in cancer research. While many cancer driver mutations have been discovered in the protein-coding genome, research into potential cancer drivers in the non-coding regions showed limited success so far. Here, we present a novel comprehensive framework Dr.Nod for detection of non-coding cis-regulatory candidate driver mutations that are associated with dysregulated gene expression using tissue-matched enhancer-gene annotations. Applying the framework to data from over 1500 tumours across eight tissues revealed a 4.4-fold enrichment of candidate driver mutations in regulatory regions of known cancer driver genes. An overarching conclusion that emerges is that the non-coding driver mutations contribute to cancer by significantly altering transcription factor binding sites, leading to upregulation of tissue-matched oncogenes and down-regulation of tumour-suppressor genes. Interestingly, more than half of the detected cancer-promoting non-coding regulatory driver mutations are over 20 kb distant from the cancer-associated genes they regulate. Our results show the importance of tissue-matched enhancer-gene maps, functional impact of mutations, and complex background mutagenesis model for the prediction of non-coding regulatory drivers. In conclusion, our study demonstrates that non-coding mutations in enhancers play a previously underappreciated role in cancer and dysregulation of clinically relevant target genes.

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Section: Discussionmentioning

confidence: 99%

Dr.Nod: computational framework for discovery of regulatory non-coding drivers in tissue-matched distal regulatory elements

Tomková

Tomek

Chow

et al. 2023

Nucleic Acids Research

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show abstract

“…It has been proven that endothelial p130cas confers resistance to antiangiogenesis therapy and targeting vascular p130cas extends survival of anti-VEGF antibody-resistant ovarian tumors. Thus, p130cas could be a target for overcoming adaptive resistance to antiangiogenic therapy [ 80 ]. Identification of resistant mechanism of bevacizumab could provide basis for overcoming drug resistance, improving prognosis and prolonging survival in ovarian cancer patients.…”

Section: Mechanisms Of Resistance and Biomarkers Of Anti-angiogenic A...mentioning

confidence: 99%

Antiangiogenic Strategies in Epithelial Ovarian Cancer: Mechanism, Resistance, and Combination Therapy

Jin

Yuan

et al. 2022

Journal of Oncology

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Angiogenesis is one of the hallmarks of cancer and plays a crucial role in carcinogenesis and progression of epithelial ovarian cancer. Antiangiogenic agent is the first approved targeted agent in ovarian cancer. Anti-angiogenic agents mainly include agents target VEGF/VEGFR pathway, such as bevacizumab and agents target receptor tyrosine kinase, and non-VEGF/VEGFR targets of angiogenesis. Antiangiogenic agents demonstrate certain effects in ovarian cancer treatment either as monotherapy or combined with chemotherapy. Unfortunately, antiangiogenic agents, such as bevacizumab, integrated into the ovarian cancer treatment paradigm do not increase cures. Thus, the benefits of anti-angiogenic agents must be carefully weighed against the cost and associated toxicities. Antiangiogenic agents drug resistance and short of predictive biomarkers are main obstacles in ovarian cancer treatment. A combination of poly (ADP-ribose) polymerase inhibitors or immune checkpoint inhibitors might be great strategies to overcome resistance as well as enhance anti-tumor activity of anti-angiogenic drugs. Predictive biomarkers of antiangiogenic agents are in urgent need.

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A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies

Zhao,

Zeng,

Kang

et al. 2024

Drug Development Research

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Drug resistance of malignant tumor leads to disease progression be the bottleneck in clinical treatment. Antiangiogenic therapy, which aims to “starve” the tumor by inhibiting angiogenesis, is one of the key strategies in clinical oncology treatments. Recently, dozens of investigational antibody drugs and biosimilars targeting angiogenesis have obtained regulatory approval for the treatment of various malignancies. Moreover, a new generation of bispecific antibodies based on the principle of antiangiogenesis are being advanced for clinical trial to overcome antiangiogenic resistance in tumor treatment or enhance the efficacy of monotherapy. Tumors often develop resistance to antiangiogenesis therapy, presenting as refractory and sometimes even resistant to new therapies, for which there are currently no effective management strategies. Thus, a detailed understanding of the mechanisms mediating resistance to antiangiogenesis antibodies is crucial for improving drug effectiveness and achieving a durable response to antiangiogenic therapy. In this review, we provide a novel perspective on the tumor microenvironment, including antibody structure, tumor stroma, and changes within tumor cells, to analyze the multifactorial reasons underlying resistance to antiangiogenesis antibodies. The review also enumerates biomarkers that indicate resistance and potential strategies for monitoring resistance. Furthermore, based on recent clinical and preclinical studies, we summarize potential strategies and translational clinical trials aimed at overcoming resistance to antiangiogenesis antibodies. This review provides a valuable reference for researchers and clinical practitioners involved in the development of new drugs or therapeutic strategies to overcome antiangiogenesis antibodies resistance.

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Endothelial p130cas confers resistance to anti-angiogenesis therapy

Cited by 5 publications

References 55 publications

Dr.Nod: computational framework for discovery of regulatory non-coding drivers in tissue-matched distal regulatory elements

Dr.Nod: computational framework for discovery of regulatory non-coding drivers in tissue-matched distal regulatory elements

Antiangiogenic Strategies in Epithelial Ovarian Cancer: Mechanism, Resistance, and Combination Therapy

A new perspective on antiangiogenic antibody drug resistance: Biomarkers, mechanisms, and strategies in malignancies

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