New Therapeutic Opportunities for the Treatment of Squamous Cell Carcinomas: A Focus on Novel Driver Kinases

Bensen, Ryan C.; Brognard, John

doi:10.3390/ijms22062831

Cited by 11 publications

(12 citation statements)

References 81 publications

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“…Copy number alterations or deletion are ubiquitous in cancer, and are associated with cancer outcomes such as recurrence and death [31]. Although some studies have suggested that copy number or deletion variations correlate with mRNA expression [32], we found that gene ampli cation of m6A family and mRNA expression were not signi cantly associated. However, we found gene alteration in 33.5% of m6A family in the TCGA database.…”

Section: Disscusioncontrasting

confidence: 61%

ZC3H13 Can Serve as Potential Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma

Liu

et al. 2021

Preprint

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Background: Recently, an increasing number of studies have revealed that N6-methyladenosine (m6A) functions as a significant post-transcriptional modification which plays a critical role in the occurrence and progression of enriched tumors by regulating coding and non-coding RNA biogenesis. However, the roles of m6A RNA modification in hepatocellular carcinoma (HCC) remain largely unknown.Results: In this study, the expression levels, genetic variations, prognostic values and gene–gene interaction network of m6A-related genes in hepatocellular carcinoma were analyzed using the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, Kaplan–Meier plotter and GeneMANIA database. The results show that zinc finger CCCH-type containing 13 (ZC3H13) was significantly lowly expressed in Hepatocellular Carcinoma. Survival outcome analysis suggested that significant correlations occurred between ZC3H13 downregulation and poor overall survival (OS) and poor recurrence free survival (RFS) in patients with liver cancer. Whereupon, ZC3H13 was selected for analyzing the biological functions and pathways of its co-expressed genes via Metascape, and its correlation with immune system responses via the TISIDB database, respectively. Further analyses indicated that ZC3H13 may be involved in transcriptional misregulation in cancer. Additionally, ZC3H13 expression was significantly correlated with lymphocytes and immunomodulators. Conclusions: Therefore, ZC3H13 is a high candidate as a novel biomarker and therapeutic target for hepatocellular carcinoma.

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Section: Disscusioncontrasting

confidence: 61%

ZC3H13 Can Serve as Potential Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma

Liu

et al. 2021

Preprint

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“…For example, distal amplification of the long arm of the third chromosome (3q26-29) is highly prevalent in SCC arising in different tissues, including lung, head and neck, and esophageal SCC. The 3q amplicon contains multiple kinase coding genes, such as PIK3CA (phosphatidylinositol 3-kinase catalytic subunit p110alpha), PRKCI [Protein Kinase C (PKC) iota], Mitogen Activated Kinase Kinase Kinase 13 ( MAP3K13) [Leucine Zipper-Bearing Kinase (LZK)], and TNIK (TRAF2- and NCK-interacting kinase) ( Bensen and Brognard, 2021 ). In some instances, a kinase regulatory protein is amplified instead of the kinase coding gene.…”

Section: Protein Kinase Amplification In Cancermentioning

confidence: 99%

Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer

Torres‐Ayuso

Brognard

2022

Mol Pharmacol

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Amplification of pro-oncogenic kinases is a common genetic alteration driving tumorigenic phenotypes. Cancer cells rely on the amplified kinases to sustain cell proliferation, survival, and growth, presenting an opportunity to develop therapies targeting the amplified kinases. Utilizing small-molecule catalytic inhibitors as therapies to target amplified kinases is plagued by de novo resistance driven by increased expression of the target, and amplified kinases can drive tumorigenic phenotypes independent of catalytic activity. Here, we discuss the emergence of proteolysis-targeting chimeras that provide an opportunity to target these oncogenic drivers effectively. SignificanceProtein kinases contribute to tumorigenesis through catalytic and non-catalytic mechanisms, and kinase gene amplifications are well-described mechanisms of resistance to small-molecule catalytic inhibitors. Repurposing catalytic inhibitors for the development of protein degraders will offer improved clinical benefits by targeting non-catalytic functions of kinases that promote tumorigenesis and overcoming resistance due to amplification.

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“…It has been described in preinvasive and invasive LUSC and represents one of the most striking differences between LUSC and LUAD 5 . Interestingly, 3q amplification is prevalent and carries prognostic relevance in head and neck, cervical, and esophageal squamous cell cancers 6 . The distal amplified area of 3q includes genes that are key in squamous differentiation such as SOX-2, p63, and PIK3CA which explains the prevalence and importance of this genetic alteration in squamous cell carcinomas 6 .…”

Section: Introductionmentioning

confidence: 99%

Brief Report: Prognostic relevance of 3q amplification in squamous cell carcinoma of the lung

Rous

Пин

Carskadon

et al. 2022

Preprint

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Introduction: Amplification of 3q is the most common genetic alteration identified in squamous cell carcinoma of the lung (LUSC) with the most frequent amplified region being 3q26-3q28. Methods: In this analysis, we aim to describe the prognostic relevance of 3q by focusing on a minimal common region (MCR) of amplification within 3q constituted by 25 genes. We analyzed 511 cases of LUSC from The Cancer Genome Atlas (TCGA) and included 476 in the final analysis. Results: We identified a 25-gene MCR that was amplified in 221 (44.3%) cases and was associated with better disease specific-survival (DSS) (NR versus 9.25 years; 95% CI [5.24-NR]; log-rank p=0.011) and a progression-free interval (PFI) of 8 years (95% CI [5.1-NR]) versus 4.9 years (95% [3.5-NR]) (Log-rank p=0.020). Multivariable analysis revealed MCR amplification was associated with improved DSS and PFI. Conclusion: Amplification of the 25-gene MCR within 3q was present in 44% of this cohort mainly composed of Caucasian patients with early-stage LUSC. This analysis is a strong indicator of the prognostic relevance of the 25-gene MCR within 3q. We are further evaluating its prognostic relevance in a racially diverse patient population with advanced LUSC.

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New Therapeutic Opportunities for the Treatment of Squamous Cell Carcinomas: A Focus on Novel Driver Kinases

Cited by 11 publications

References 81 publications

ZC3H13 Can Serve as Potential Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma

ZC3H13 Can Serve as Potential Prognostic Biomarker and Therapeutic Target for Hepatocellular Carcinoma

Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer

Brief Report: Prognostic relevance of 3q amplification in squamous cell carcinoma of the lung

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