Comprehensive pancancer genomic analysis reveals (RTK)-RAS-RAF-MEK as a key dysregulated pathway in cancer: Its clinical implications

Imperial, Robin; Toor, Omer M.; Hussain, Arif; Subramanian, Janakiraman; Masood, Ashiq

doi:10.1016/j.semcancer.2017.11.016

Cited by 61 publications

(55 citation statements)

References 184 publications

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“…Importantly, activation of IL‐2Rβ is also capable of activating PLCγ/Raf/MAPK signalling pathway, which plays a pivotal role in regulating cell proliferation and survival . ERK(ERK1/2) and p38 MAPK, two of the major classical MAPK pathway, have been proposed as targets in cancer therapy as a result of abnormal activation . Results showed that TPD7 significantly decreased the level of p‐PLCγ, Raf, p‐MEK1/2 and p‐ERK1/2, while increased the level of p‐p38 and p53 (Figure ).…”

Section: Discussionmentioning

confidence: 99%

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

Zhu

Liu

Shi

et al. 2019

J Cellular Molecular Medi

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IL‐2R pathway is a key regulator in the development of immune cells and has emerged as a promising drug target in cancer treatment, but there is a scarcity of related inhibitors. TPD7 is a novel biphenyl urea taspine derivate, which has been shown anti‐cancer effect. Here, we demonstrated the anti‐cancer activity of TPD7 in cutaneous T cell lymphoma and investigated the underlying mechanism of TPD7 through IL‐2R signalling. The inhibitory effect of TPD7 on cell viability exhibited a strong correlation with the expression level of IL‐2R, and cutaneous T cell lymphoma H9 and HUT78 cells were most sensitive to TPD7. TPD7 was nicely bound to IL‐2R and down‐regulated the mRNA and protein levels of IL‐2R. Furthermore, TPD7 suppressed the downstream cascades of IL‐2R including JAK/STAT, PI3K/AKT/mTOR and PLCγ/Raf/MAPK signalling, resulting in Bcl‐2 mitochondrial apoptosis pathway and cell cycle proteins CDK/Cyclins regulation. And, these were verified by flow cytometry analysis that TPD7 facilitated cell apoptosis in H9 cells via mitochondrial pathway and impeded cell cycle progression at G2/M phase. TPD7 is a novel anti‐cancer agent and may be a potential candidate for cutaneous T cell lymphoma treatment by regulating IL‐2R signalling pathway.

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Section: Discussionmentioning

confidence: 99%

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

Zhu

Liu

Shi

et al. 2019

J Cellular Molecular Medi

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“…MAPK signaling is associated with cell proliferation, invasion capacity and EMT . The NGS results also indicated that MAPK signaling was most affected (Figure A and B).…”

Section: Resultsmentioning

confidence: 81%

“…MAPK signaling is associated with cell proliferation, invasion capacity and EMT. [12][13][14] The NGS results also indicated that MAPK signaling was most affected ( Figure 3A and 3B). By Western blot, lncRNA DRHC attenuated the phosphorylation of ERK1/2 and its upstream factor MEK1/2, whereas the phosphorylation levels of JNK and p38 remained unchanged in Huh-7 and SK-Hep-1 cells ( Figure 3C).…”

Section: Lncrna Drhc Inhibited Mek/erk Signaling In Hccmentioning

confidence: 82%

lncRNA DRHC inhibits proliferation and invasion in hepatocellular carcinoma via c‐Myb‐regulated MEK/ERK signaling

Zhuang

Zhang

et al. 2018

Molecular Carcinogenesis

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Accumulating evidence indicates that long non‐coding RNAs (lncRNAs) play a crucial role in hepatocellular carcinoma (HCC). Here, we reported a novel lncRNA, CTC‐505O3 (lncRNA DRHC), that was downregulated in HCC and its low expression was associated with dismal survival. Gain‐of‐function studies indicated that it inhibited proliferation, migration, invasion, and epithelial‐mesenchymal transition (EMT) in HCC cell lines in vitro. lncRNA DRHC also inhibited tumorigenicity in vivo. In mechanistic experiments, GO analysis based on NGS indicated that MAPK signaling was most affected. The result was confirmed by Western blot and this effect was abolished either by MEK1/2 specific inhibitor Trametinib or ERK1/2 inhibitor SCH772984. In addition, differences in proliferation and invasion were abrogated by Trametinib. Moreover, we found that lncRNA DRHC interacted with MYBBP1A and modulated MEK/ERK signaling via c‐Myb. Taken together, our findings indicate that the lncRNA DRHC play a key role in HCC progression and may serve as a novel therapeutic target.

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“…Mutations at these residues affect the protein’s ability to hydrolyze GTP leading to constitutive activity and downstream signaling. [31] We found these mutations were enriched in RCC compared to LCC and rectal cancers in both the TCGA and the metastatic MSKCC data (all p <0.05). In addition, we found APC R1450* to be a significant mutation in colorectal cancers.…”

Section: Resultsmentioning

confidence: 84%

“…[47] Similarly, understanding discrepancies in RAS mutations between primary and metastatic sites is relevant since studies have shown that CRC with wild-type RAS responds better to anti-EGFR therapy plus systemic chemotherapy compared to CRC with mutant RAS. [31]…”

Section: Discussionmentioning

confidence: 99%

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

Imperial

Ahmed

Toor

et al. 2018

Preprint

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To understand the molecular differences between right-sided colon cancer (RCC), left-sided colon cancer (LCC) and rectal cancer, we analyzed colorectal tumors at the DNA, RNA, miRNA and protein levels using previously sequenced data from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center. Clonal evolution analysis identified the same tumor-initiating events involving APC, KRAS and TP53 genes in RCC, LCC and rectal cancers. However, the individual role-played by each event, their order in tumor dynamics and selection of downstream mutations were distinct in all three anatomical locations, with some similarities noted between LCC and rectal cancer. We found a potentially targetable alteration APC R1450* specific to RCC that has not been previously described. Differential gene expression analysis revealed multiple genes within the homeobox, G-protein coupled receptor binding and transcription regulation families were dysregulated in RCC, LCC, and rectal cancers and may have a pathological role in these cancers. Further, using a novel in silico proteomic analytic tool developed by our research group, we found distinct central or hub proteins with unique interactomes in each location. Protein expression signatures were not necessarily concordant with the tumor profiles obtained at the DNA and RNA levels, underscoring the relevance of post-transcriptional events in defining the biology of these cancers beyond molecular changes at the DNA and/or RNA level. Ultimately, not only tumor location and the respective genomic profile but also protein-protein interactions will need to be taken into account to improve treatment outcomes of colorectal cancers. Further studies that take into account the alterations found in this study may help in developing more tailored, and perhaps more effective, treatment strategies.Author summaryPatients with right-sided colon cancer (RCC) has a worse prognosis compared to left-sided colon cancer (LCC). Recent data has also shown that wild-type RAS metastatic RCC’s have poor outcomes when treated with the combination of chemotherapy and anti-EGFR therapy compared to LCC and rectal cancers. Therefore, There is an urgent unmet need to understand the molecular differences between RCC, LCC, and rectal cancers. In this study, we demonstrate clonal evolutionary trajectory and the order of mutations in RCC, LCC, and rectal cancers are distinct with some similarities between LCC and rectal cancers. The order of the mutations that lead to the acquisition of crucial driver alterations may have prognostic and therapeutic implications. We also discovered a novel targetable alteration, APC R1450* to be significantly enriched in early, late and metastatic RCC but not in LCC and rectal cancers. Amazingly, proteomic signatures were discordant with DNA and RNA levels. These distinct differences in DNA, RNA and post-transcriptional events may contribute to their unique clinicopathological features.Conflict of Interest StatementAshiq Masood Advisory board and speaker Bureau Bristol-Myers Squibb and Boehringer IngelheimJanakiraman Subramanian Advisory board - Astra Zeneca, Pfizer, Boehringer Ingelheim, Alexion, Paradigm, Bristol-Myers Squibb Speakers Bureau - Astra Zeneca, Boehringer Ingelheim, Lilly Research Support - Biocept and ParadigmArif Hussain Advisory board – Novartis, Bayer, Astra Zeneca Consultant – Bristol-Myers-Squibb All other authors have no conflict of interest.

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Comprehensive pancancer genomic analysis reveals (RTK)-RAS-RAF-MEK as a key dysregulated pathway in cancer: Its clinical implications

Cited by 61 publications

References 184 publications

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

TPD7 inhibits the growth of cutaneous T cell lymphoma H9 cell through regulating IL‐2R signalling pathway

lncRNA DRHC inhibits proliferation and invasion in hepatocellular carcinoma via c‐Myb‐regulated MEK/ERK signaling

Comparative Proteogenomic Analysis of Right-sided Colon Cancer, Left-sided Colon Cancer and Rectal Cancers Reveal Distinct Mutational Profiles

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