Combing the Cancer Genome for Novel Kinase Drivers and New Therapeutic Targets

Torres‐Ayuso, Pedro; Brognard, John

doi:10.3390/cancers11121972

Cited by 10 publications

(6 citation statements)

References 118 publications

(137 reference statements)

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“…with small-molecule catalytic inhibitors, it is necessary to address whether cancer cells could become resistant to PROTACs. For example, cancer cells can develop mutations that reduce the pharmacophore's binding affinity to its intended target (Lovly and Shaw, 2014;Torres-Ayuso and Brognard, 2019); consistent with this mechanism of resistance, mutations in the protein of interest can render it resistant to PROTAC-mediated degradation, as recently shown for CDK12 (Jiang et al, 2021). Nonetheless, because target degradation efficacy does not correlate with the PROTAC binding affinity to its target, PROTACs could still effectively degrade these novel variants.…”

Section: Besides the Pharmacological Properties Of Protacs And Based ...mentioning

confidence: 87%

“…Mutations in kinase coding genes or chromosomal rearrangements leading to fused genes are common genetic alterations that cause cancer. Amplification of prosurvival and proproliferation kinase coding genes is another common mechanism driving cancer with a resulting increase in kinase levels and often a correlating increase in activation ( Torres-Ayuso and Brognard, 2019 ). There are multiple examples of amplified tyrosine protein kinases playing a causal role in tumorigenesis, including the epidermal growth factor receptor (EGFR) family members, which is amplified in 30%–40% of glioblastomas and other epithelial malignancies at a lower frequency ( Schlegel et al, 1994 ; Hynes and Lane, 2005 ), and ERBB2 (also known as HER2/neu), which is amplified in 15%–30% of breast cancers ( Harari and Yarden, 2000 ; Perou et al, 2000 ) and approximately 10%–15% of esophageal and stomach adenocarcinomas ( Cancer Genome Atlas Research Network, 2014 ).…”

Section: Protein Kinase Amplification In Cancermentioning

confidence: 99%

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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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Section: Besides the Pharmacological Properties Of Protacs And Based ...mentioning

confidence: 87%

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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“…In addition, numerous cell cycle-controlling genes are overexpressed in ESCC. For example, cyclin-dependent kinase 4/cyclin-dependent kinase 6 accounted for 23.6%, murine double minute 25.7%, and cyclin D1 46.4%, showing that the above components are implicated in the incidence and development of ESCC[ 9 ]. As a result, there is a pressing need to uncover genetic anomalies in esophageal cancer and understand their molecular basis to enhance early diagnosis and minimize esophageal cancer mortality.…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of the relationship between cuproptosis-related genes and esophageal cancer prognosis

Xu¹,

Du²,

Wang³

et al. 2022

World J Clin Cases

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BACKGROUND Esophageal cancer is one of the most common malignant tumors of the digestive system, with a 5-year survival rate of 15% to 50%. Cuproptosis, a unique kind of cell death driven by protein lipoylation, is strongly connected to mitochondrial metabolism. The clinical implications of cuproptosis-related genes in esophageal cancer, however, are mainly unknown. AIM To identify cuprotosis-related genes that are differentially expressed in esophageal cancer and investigate their prognostic significance. METHODS With |log fold change| > 1 and false discovery rate < 0.05 as criteria, the Wilcox test was used to evaluate the differentially expressed genes between 151 tumor tissues and 151 normal esophageal tissues. Cuproptosis-related genes were selected to be linked with prognosis using univariate Cox regression analysis. Genes were separated into high- and low- expression groups based on their cutoff value of gene expression, and the correlation between the two groups and overall survival or progression-free survival was investigated using the log-rank test. The C-index, calibration curve, and receiver operator characteristic (ROC) curve were used to assess a nomogram containing clinicopathological characteristics and cuproptosis-related genes. RESULTS Pyruvate dehydrogenase A1 (PDHA1) was found to be highly correlated with prognosis in univariate Cox regression analysis (hazard ratio = 22.96, 95% confidence interval = 3.09-170.73; P = 0.002). According to Kaplan-Meier survival curves, low expression of PDHA1 was associated with a better prognosis (log-rank P = 0.0007). There was no significant correlation between PDHA1 expression and 22 different types of immune cells. Tumor necrosis factor superfamily member 15 (TNFSF15) ( P = 3.2 × 10 -6 ; r = 0.37), TNFRSF14 ( P = 8.1 × 10 -8 ; r = 0.42), H long terminal repeat-associating 2 ( P = 6.0 × 10 -8 ; r = 0.42) and galectin 9 ( P = 3.1 × 10 -6 ; r = 0.37) were all found to be considerably greater in the high PDHA1 expression group, according to an analysis of genes related to 47 immunological checkpoints. The low PDHA1 expression group had significantly lower levels of cluster of differentiation 44 (CD44) ( P = 0.00028; R = -0.29), TNFRSF18 ( P = 1.2 × 10 -5 ; R = -0.35), programmed cell death 1 ligand 2 ( P = 0.0032; R = -0.24), CD86 ( P = 0.018; R = -0.19), and CD40 ( P = 0.0047; R = -0.23), and the differences were statistically...

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“…The promising data from targeting BCR-ABL1 in CML encouraged the exploration of novel inhibitors for other cancers with known oncogenic drivers [5]. However, to date, the development of targeted inhibitors for other malignancies has not proven as successful as imatinib, partly due to the presence of several genomic abnormalities contributing to the development of most other types of cancers.…”

Section: Introductionmentioning

confidence: 99%

Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia

Ribeiro

Eiring

Khorashad

2021

Cancers

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Acute myeloid leukemia (AML) is a highly heterogeneous malignancy characterized by the clonal expansion of myeloid stem and progenitor cells in the bone marrow, peripheral blood, and other tissues. AML results from the acquisition of gene mutations or chromosomal abnormalities that induce proliferation or block differentiation of hematopoietic progenitors. A combination of cytogenetic profiling and gene mutation analyses are essential for the proper diagnosis, classification, prognosis, and treatment of AML. In the present review, we provide a summary of genomic abnormalities in AML that have emerged as both markers of disease and therapeutic targets. We discuss the abnormalities of RARA, FLT3, BCL2, IDH1, and IDH2, their significance as therapeutic targets in AML, and how various mechanisms cause resistance to the currently FDA-approved inhibitors. We also discuss the limitations of current genomic approaches for producing a comprehensive picture of the activated signaling pathways at diagnosis or at relapse in AML patients, and how innovative technologies combining genomic and functional methods will improve the discovery of novel therapeutic targets in AML. The ultimate goal is to optimize a personalized medicine approach for AML patients and possibly those with other types of cancers.

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Combing the Cancer Genome for Novel Kinase Drivers and New Therapeutic Targets

Cited by 10 publications

References 118 publications

Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer

Degraders: The Ultimate Weapon Against Amplified Driver Kinases in Cancer

Comprehensive analysis of the relationship between cuproptosis-related genes and esophageal cancer prognosis

Genomic Abnormalities as Biomarkers and Therapeutic Targets in Acute Myeloid Leukemia

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