Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma

Sager, Rebecca; Backe, Sarah J.; Ahanin, Elham; Smith, Garrett; Nsouli, Imad; Woodford, Mark R.; Bratslavsky, Gennady; Bourboulia, Dimitra; Mollapour, Mehdi

doi:10.1038/s41585-022-00571-8

Cited by 17 publications

(10 citation statements)

References 234 publications

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“…CDK4 and other cell cycle regulation proteins could be attenuated by the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) antagonist [ 46 ]. CDK4 is a very promising therapeutical target, but there is much more investigation needed with present therapeutics counting immune checkpoint inhibitors [ 47 ].…”

Section: Discussionmentioning

confidence: 99%

Signatures of Co-Deregulated Genes and Their Transcriptional Regulators in Kidney Cancers

Ioannou

Chatziantoniou

Drenios

et al. 2023

IJMS

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There are several studies on the deregulated gene expression profiles in kidney cancer, with varying results depending on the tumor histology and other parameters. None of these, however, have identified the networks that the co-deregulated genes (co-DEGs), across different studies, create. Here, we reanalyzed 10 Gene Expression Omnibus (GEO) studies to detect and annotate co-deregulated signatures across different subtypes of kidney cancer or in single-gene perturbation experiments in kidney cancer cells and/or tissue. Using a systems biology approach, we aimed to decipher the networks they form along with their upstream regulators. Differential expression and upstream regulators, including transcription factors [MYC proto-oncogene (MYC), CCAAT enhancer binding protein delta (CEBPD), RELA proto-oncogene, NF-kB subunit (RELA), zinc finger MIZ-type containing 1 (ZMIZ1), negative elongation factor complex member E (NELFE) and Kruppel-like factor 4 (KLF4)] and protein kinases [Casein kinase 2 alpha 1 (CSNK2A1), mitogen-activated protein kinases 1 (MAPK1) and 14 (MAPK14), Sirtuin 1 (SIRT1), Cyclin dependent kinases 1 (CDK1) and 4 (CDK4), Homeodomain interacting protein kinase 2 (HIPK2) and Extracellular signal-regulated kinases 1 and 2 (ERK1/2)], were computed using the Characteristic Direction, as well as GEO2Enrichr and X2K, respectively, and further subjected to GO and KEGG pathways enrichment analyses. Furthermore, using CMap, DrugMatrix and the LINCS L1000 chemical perturbation databases, we highlight putative repurposing drugs, including Etoposide, Haloperidol, BW-B70C, Triamterene, Chlorphenesin, BRD-K79459005 and β-Estradiol 3-benzoate, among others, that may reverse the expression of the identified co-DEGs in kidney cancers. Of these, the cytotoxic effects of Etoposide, Catecholamine, Cyclosporin A, BW-B70C and Lasalocid sodium were validated in vitro. Overall, we identified critical co-DEGs across different subtypes in kidney cancer, and our results provide an innovative framework for their potential use in the future.

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Section: Discussionmentioning

confidence: 99%

Signatures of Co-Deregulated Genes and Their Transcriptional Regulators in Kidney Cancers

Ioannou

Chatziantoniou

Drenios

et al. 2023

IJMS

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“…These data suggest that a combination of immune checkpoint inhibitors and mTOR inhibitors may be more effective. In fact, many pharmaceutical companies are conducting clinical trials of combinations of PI3K/mTOR inhibitors and immune checkpoint inhibitors [ 97 , 98 , 99 ]. mTOR is required for Th1 and Th2 effector T cell differentiation.…”

Section: Cancer Therapy By Targeting Mtormentioning

confidence: 99%

Targeting mTOR for Anti-Aging and Anti-Cancer Therapy

2023

Molecules

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The balance between anabolism and catabolism is disrupted with aging, with the rate of anabolism being faster than that of catabolism. Therefore, mTOR, whose major function is to enhance anabolism and inhibit catabolism, has become a potential target of inhibition for anti-aging therapy. Interestingly, it was found that the downregulation of the mTOR signaling pathway had a lifespan-extending effect resembling calorie restriction. In addition, the mTOR signaling pathway promotes cell proliferation and has been regarded as a potential anti-cancer target. Rapamycin and rapalogs, such as everolimus, have proven to be effective in preventing certain tumor growth. Here, we reviewed the basic knowledge of mTOR signaling, including both mTORC1 and mTORC2. Then, for anti-aging, we cited a lot of evidence to discuss the role of targeting mTOR and its anti-aging mechanism. For cancer therapy, we also discussed the role of mTOR signaling in different types of cancers, including idiopathic pulmonary fibrosis, tumor immunity, etc. In short, we discussed the research progress and both the advantages and disadvantages of targeting mTOR in anti-aging and anti-cancer therapy. Hopefully, this review may promote more ideas to be generated for developing inhibitors of mTOR signaling to fight cancer and extend lifespan.

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“…With respect to focal changes detected by GISTIC2 (Figure 4B,C and supplementary material, Table S9), the frequently amplified regions included 5p15.33 (9/51,17.6%), which harbors ZDHHC11 (encoding a key component of the oncogenic MYC-miR-150-MYB network implicated in cancer); 17q12 (9/51,17.6%), which contains CCL3L1, CCL4L, CCL3L3, and two paralogs of the known oncogene TBC1D3; and 12q14.1(7/51, 13.7%), which encompasses the known oncogenes CDK4 and AGAP2. The sustained cell proliferation resulting from dysregulation of the cell cycle and activation of cyclin-dependent kinases (CDKs) is a hallmark of cancer, and previous studies revealed that inhibitors targeting CDK4 and/or its homolog, CDK6, both of which play a key role in retinoblastoma protein (RB) phosphorylation, showed promising treatment effects in multiple cancers, including, for example, breast cancer, renal cell carcinoma, and GBM [43][44][45][46]; therefore, we further manually reviewed alterations in key genes within the RB pathway, including CDKN2A/B, CDK6, cyclin D genes (CCND1, CCND2, and CCND3), and RB1, and the results revealed that three patients had homozygous deletion of CDKN2A/B, five patients harbored amplification of CDK6, five patients had amplification of CCND1, four patients carried amplification of CCND3, five patients showed homozygous deletion of RB1, and no SNVs occurred in these genes. Taken together, focal CNVs in RB pathway regulatory components, including CDKN2A/B, CDK4, CDK6, cyclin D genes, and RB1, were found in 20 (39.2%) of 51 primary SCAs.…”

Section: Copy Number Analysismentioning

confidence: 99%

Mutational landscape of primary spinal cord astrocytoma

Cheng

Zhang

Zhao

et al. 2023

The Journal of Pathology

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Primary spinal cord astrocytoma (SCA) is a rare disease. Knowledge about the molecular profiles of SCAs mostly comes from intracranial glioma; the pattern of genetic alterations of SCAs is not well understood. Herein, we describe genome‐sequencing analyses of primary SCAs, aiming to characterize the mutational landscape of primary SCAs. We utilized whole exome sequencing (WES) to analyze somatic nucleotide variants (SNVs) and copy number variants (CNVs) among 51 primary SCAs. Driver genes were searched using four algorithms. GISTIC2 was used to detect significant CNVs. Additionally, recurrently mutated pathways were also summarized. A total of 12 driver genes were identified. Of those, H3F3A (47.1%), TP53 (29.4%), NF1 (19.6%), ATRX (17.6%), and PPM1D (17.6%) were the most frequently mutated genes. Furthermore, three novel driver genes seldom reported in glioma were identified: HNRNPC, SYNE1, and RBM10. Several germline mutations, including three variants (SLC16A8 rs2235573, LMF1 rs3751667, FAM20C rs774848096) that were associated with risk of brain glioma, were frequently observed in SCAs. Moreover, 12q14.1 (13.7%) encompassing the oncogene CDK4 was recurrently amplified and negatively affected patient prognosis. Besides frequently mutated RTK/RAS pathway and PI3K pathway, the cell cycle pathway controlling the phosphorylation of retinoblastoma protein (RB) was mutated in 39.2% of patients. Overall, a considerable degree of the somatic mutation landscape is shared between SCAs and brainstem glioma. Our work provides a key insight into the molecular profiling of primary SCAs, which might represent candidate drug targets and complement the molecular atlas of glioma. © 2023 The Pathological Society of Great Britain and Ireland.

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Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma

Cited by 17 publications

References 234 publications

Signatures of Co-Deregulated Genes and Their Transcriptional Regulators in Kidney Cancers

Signatures of Co-Deregulated Genes and Their Transcriptional Regulators in Kidney Cancers

Targeting mTOR for Anti-Aging and Anti-Cancer Therapy

Mutational landscape of primary spinal cord astrocytoma

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