Dual inhibition of CDK4 and FYN leads to selective cell death in KRAS-mutant colorectal cancer

Wang, Yan; Lin, Rongjie; Ling, Huan; Yuan, Ke; Zeng, Yongquan; Xiong, Yudi; Zhou, Qian; Zhou, Fuxiang; Zhou, Youwen

doi:10.1038/s41392-019-0088-z

Cited by 7 publications

(6 citation statements)

References 7 publications

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“…Thus cell cycle re-entry requires concerted processes that involve not only canonical phosphorylation events by CDK1 of a wide range of targets that regulate centrosome maturation, nuclear envelope breakdown and spindle assembly during mitosis, but also CDK1-mediated licensing of K-Ras-signaling [ 74 ]. This connection is particularly interesting, considering that other CDKs, such as CDK4, cooperate with K-Ras in tumorigenesis [ 75 , 76 ]. With the above-mentioned regulation of the SPRED1/NF1 interaction by CDK1 during the cell cycle in mind, a continuous inhibition of CDKs may work for short bouts of cancer therapy, but not long-term for the treatment of typically younger RASopathy patients.…”

Section: Ras-mapk-signaling In Stem Cell Priming and In Developmentalmentioning

confidence: 99%

Promotion of cancer cell stemness by Ras

Chippalkatti

Abankwa

2021

Biochemical Society Transactions

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Cancer stem cells (CSC) may be the most relevant and elusive cancer cell population, as they have the exquisite ability to seed new tumors. It is plausible, that highly mutated cancer genes, such as KRAS, are functionally associated with processes contributing to the emergence of stemness traits. In this review, we will summarize the evidence for a stemness driving activity of oncogenic Ras. This activity appears to differ by Ras isoform, with the highly mutated KRAS having a particularly profound impact. Next to established stemness pathways such as Wnt and Hedgehog (Hh), the precise, cell cycle dependent orchestration of the MAPK-pathway appears to relay Ras activation in this context. We will examine how non-canonical activities of K-Ras4B (hereafter K-Ras) could be enabled by its trafficking chaperones calmodulin and PDE6D/PDEδ. Both dynamically localize to the cellular machinery that is intimately linked to cell fate decisions, such as the primary cilium and the centrosome. Thus, it can be speculated that oncogenic K-Ras disrupts fundamental polarized signaling and asymmetric apportioning processes that are necessary during cell differentiation.

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Section: Ras-mapk-signaling In Stem Cell Priming and In Developmentalmentioning

confidence: 99%

Promotion of cancer cell stemness by Ras

Chippalkatti

Abankwa

2021

Biochemical Society Transactions

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“…FYN knockdown or inhibition significantly reduces proliferation, migration, metastasis, and invasion in pancreatic cancer models [ 22 , 156 ]. Recent data suggest FYN associated pancreatic tumor pathology may depend on KRAS and TP53 mutational profiles [ 13 , 202 ].…”

Section: Fyn Proto-oncogene Kinase (Fyn)mentioning

confidence: 99%

“…Mechanistic studies exploring the signaling axis of FYN in pancreatic cancer suggest significant modulation of cell cycle and apoptotic behaviors [ 156 , 157 , 158 ]. Mechanistic studies in other cancer models suggest inhibition of FYN leads to greater cell death in KRAS mutant cells than in KRAS wild-type cells [ 202 ]. Other cancer models also provide evidence that FYN phosphorylates and enhances the activity of the GTPase PIKE-A, ultimately influencing p53 behavior ( Figure 1 ).…”

Section: Fyn Proto-oncogene Kinase (Fyn)mentioning

confidence: 99%

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

Creeden

Alganem

Imami

et al. 2020

IJMS

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Kinase drug discovery represents an active area of therapeutic research, with previous pharmaceutical success improving patient outcomes across a wide variety of human diseases. In pancreatic ductal adenocarcinoma (PDAC), innovative pharmaceutical strategies such as kinase targeting have been unable to appreciably increase patient survival. This may be due, in part, to unchecked desmoplastic reactions to pancreatic tumors. Desmoplastic stroma enhances tumor development and progression while simultaneously restricting drug delivery to the tumor cells it protects. Emerging evidence indicates that many of the pathologic fibrotic processes directly or indirectly supporting desmoplasia may be driven by targetable protein tyrosine kinases such as Fyn-related kinase (FRK); B lymphoid kinase (BLK); hemopoietic cell kinase (HCK); ABL proto-oncogene 2 kinase (ABL2); discoidin domain receptor 1 kinase (DDR1); Lck/Yes-related novel kinase (LYN); ephrin receptor A8 kinase (EPHA8); FYN proto-oncogene kinase (FYN); lymphocyte cell-specific kinase (LCK); tec protein kinase (TEC). Herein, we review literature related to these kinases and posit signaling networks, mechanisms, and biochemical relationships by which this group may contribute to PDAC tumor growth and desmoplasia.

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“…Although the treatment of CRC has been continuously optimized as medical technology has advanced, there is still no effective treatment for patients with advanced metastatic CRC. One of the basic processes during CRC occurrence and development is the accumulation of various genetic and epigenetic changes in colonic epithelial cells [ 3 , 4 ]. Epigenetic modifications, including DNA methylation, histone modification, nucleosome remodeling, and RNA modification [ 5 ], regulate cell self-renewal, differentiation, invasion, and apoptosis by modulating gene expression [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of lncRNAs N6-methyladenosine modification in colorectal cancer

Zuo

Zhang

et al. 2021

Aging

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Background: Long non-coding RNAs (lncRNAs) and their N6-methyladenosine (M6A) modifications are involved in cancer occurrence and development. Methods: lncRNA M6A modification in colorectal cancer (CRC) was comprehensively analyzed for the first time. Results: M6A levels of lnRNAs in CRC tissues were higher than those in tumor-adjacent normal tissues. A total of 8,332 M6A peaks were detected in 6,690 lncRNAs in CRC tissues. Approximately 91% of the modified lncRNAs had unique M6A modification peaks. A total of 383 lncRNAs were differentially methylated in CRC, of which 48.24% had a length of 1-1,000 bp. Most of these were located on chromosomes 1, 2, 7, 11, 16 and 19; 42.3% were within a sense-overlapping exon. RNA sequencing identified 163 differentially expressed lncRNAs in CRC. GO and KEGG analyses revealed that genes near differentially-methylated or -expressed lncRNAs were associated with CRC occurrence and development. Methylation was positively correlated with lncRNA expression levels in CRC and tumor-adjacent normal tissues. More unmethylated than M6A methylated lncRNA molecules were detected. A competing endogenous RNA (ceRNA) and lncRNA-mRNA expression-regulation network revealed a regulatory relationship between lncRNAs, microRNAs (miRNAs), and mRNAs. Conclusions: The findings may help improve our understanding of lncRNA function in colorectal cancer.

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Dual inhibition of CDK4 and FYN leads to selective cell death in KRAS-mutant colorectal cancer

Cited by 7 publications

References 7 publications

Promotion of cancer cell stemness by Ras

Promotion of cancer cell stemness by Ras

Emerging Kinase Therapeutic Targets in Pancreatic Ductal Adenocarcinoma and Pancreatic Cancer Desmoplasia

Comprehensive analysis of lncRNAs N6-methyladenosine modification in colorectal cancer

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