CDK4 overexpression

Our data strongly support investigation of the chemotherapy-free palbociclib and venetoclax combination as an innovative treatment strategy for post-ibrutinib MCL patients without RB1 deletion.

In addition, high CDK4 expression and cell cycle variability were observed in AM, with high immunogenicity in NAM. Overall, these findings provide further insights into the pathogenesis of melanoma and serve as a reference for future research on this major malignant disease.

P2, N=40, Recruiting, Grupo Espanol de Investigacion en Sarcomas | Trial completion date: Dec 2023 --> Sep 2024 | Trial primary completion date: Dec 2023 --> Sep 2024

This study suggests a relationship between CDK4 and immune infiltration and prognosis in HCC. Additionally, a CDK4 inhibitor may have anti-tumor properties against hepatocellular cancer.

Translational research showed a significant correlation between CDK4 mRNA and protein expression. Palbociclib was active in a variety of sarcoma subtypes, selected by CDK4/CDKN2A, and deserves further investigation in the sarcoma context.

In this study, the overexpression/knockdown CDK4 and negative control group were successfully constructed in H1339 and SW1271 cells, revealing the radiotherapy resistance of CDK4 alterations in vitro and in vivo experiment. And CDK4 alterations was shown to promote radiotherapy resistance through phosphorylation of MAPK/ERK signaling pathway in SCLC.

Importantly, the inhibitory effects of METTL1 knockdown on the proliferation of HNSC, esophageal cancer (ESCA), stomach adenocarcinoma (STAD), and colon adenocarcinoma (COAD) were significantly mitigated by over-expression of CDK4. Taken together, this study expands the understanding of epigenetic mechanisms involved in tumorigenesis and identifies the METTL1/CDK4 axis as a potential therapeutic target for digestive system tumors.

We identified overexpressers of CDK and cyclin genes among a heterogeneous sample of sarcoma patients. By setting a threshold of 2 SD above the mean of each gene we captured the top ~2% of expressers, and by considering subtypes with ≥ 25% of cases above that threshold we accurately identified known associations between CDK4/LPS and CCND1/Ewing sarcoma while also revealing new associations. The most notable overexpressers were chordoma (CDK7, CDK18), CCS (CDK2, CCNA1), RCS (CCND2), and RMS (CDK6, CDK8, CCND2, CCNE1).

Rescue function experiments corroborated that the anticancer activities of TFAP2A-AS1 deficient on the oncogenicity of NSCLC cells were reversed by downregulating miR-584-3p or overexpressing CDK4. To sum up, TFAP2A-AS1 exhibits cancer-promoting roles in NSCLC through the adjustment of miR-584-3p/CDK4 axis.

Sanguinarine inhibits the proliferation and invasion of HCC cells, and induces the apoptosis of HCC cells by regulating the expression of miR-497-5p/CDK4.

Experimental therapy aimed at inhibition of CDK by palbociclib and anti-apoptotic BCL-2 proteins using venetoclax, S63845 and A1155463 was performed on nine MCL cell lines and four patient-derived xenograft (PDX) models from patients with R/R MCL. Our data strongly support investigation of palbociclib in combination with venetoclax as an innovative treatment strategy for chemoresistant MCL patients without RB1 deletion. Although we demonstrated that palbociclib increases pro-apoptotic mitochondrial priming and induces metabolic stress, the detailed contribution of these changes to the observed synergy are under investigation.

The median PFS was 4 and 7 months for palbociclib and abemaciclib, respectively. Palbociclib showed to be effective in a wide variety of sarcoma subtypes, other than DD LPS, selected by CDK4/CDKN2A biomarkers

Orthotopic xenografts of N-Myc-overexpressing retinal cells formed tumors with retinal cell marker expression similar to those in MYCN-transduced retinae and MYCN retinoblastomas in patients. These findings demonstrate the MYCN retinoblastoma origin from immature and lineage-deconstrained cone precursors, reveal their opportunistic use of an undifferentiated retinal progenitor cell feature, and illustrate that different cancer-initiating mutations cooperate with distinct developmental stage-specific cell signaling circuitries to drive retinoblastoma tumorigenesis.

Among the different groups of CDKs, CDK4 overexpression/hyperactivation is found to be present in many cancers and a specific CDK4 inhibitor, palbociclib has been recently approved by the FDA against breast cancer...We screened the compounds using Lipinski's rule, ADMET analysis and further analyzed the selected compounds using a virtual screening method called molecular docking and validated our results by MD simulation. We studied the expression patterns and prognostic significance of CDK4 across multiple carcinomas by using some database like UALCAN, cBioportal, and KM-Plotter.

5-Fluorouracil (5-FU) is a commonly applied therapeutic drug in colon cancer patient regimens; however, the majority of patients develop resistance to 5-FU in the later stages of the disease, rendering this chemotherapy ineffective...On the whole, the findings of the present study suggest that PVT1 promotes the resistance of colon cancer cells to 5-FU by regulating the miR-486-5p/CDK4 axis. Therefore, PVT1 may prove to be a potential target for counteracting resistance to 5-FU in colon cancer therapy.

Rescue function experiments corroborated that the anticancer activities of TFAP2A AS1 deficient on the oncogenicity of NSCLC cells were reversed by downregulating miR 584 3p or overexpressing CDK4. To sum up, TFAP2A AS1 exhibits cancer promoting roles in NSCLC through the adjustment of miR 584 3p/CDK4 axis.

P2, N=40, Recruiting, Grupo Espanol de Investigacion en Sarcomas | Trial completion date: Dec 2020 --> Dec 2023 | Trial primary completion date: Dec 2020 --> Dec 2023

The combination of ribociclib and everolimus following radiotherapy in children with newly diagnosed DIPG and HGG was well tolerated, with a RP2D of ribociclib 170 mg/m and everolimus 1.5 mg/m. Results will inform a molecularly guided phase II study underway to evaluate efficacy.

The median PFS was 4 and 7 months (m) for palbociclib and abemaciclib, respectively. Palbociclib showed to be effective in a wide variety of sarcoma subtypes, other than DD LPS, selected by CDK4/CDKN2A biomarkers.

HCC patients with high CDK4 expression have poor prognosis, and CDK4 could be a potential candidate diagnostic biomarker for HCC.

By decreasing the expression of cdk4 and p16, pimecrolimus, methotrexate, and mycophenolate mofetil decrease the malignant potential of OLP lesions. However, methorexate can be a better alternative in cases showing high cdk4 expression.

Overexpression of CDK4/6 or Rb1 knockout confers neuroblastoma cell resistance to both palbociclib and the KDM6 inhibitor GSK-J4. These data indicate that KDM6B promotes an oncogenic CDK4/6-pRB-E2F pathway in neuroblastoma cells via H3K27me3-dependent enhancer-promoter interactions, providing a rationale to target KDM6B for high-risk neuroblastoma.

Indeed, using two-dimensional (n = 7) and three-dimensional (n = 3) cultures of human osteosarcoma cell lines, it was shown that osteosarcoma cells with defective p16 are sensitive to the CDK4/CDK6 inhibitor palbociclib after 72-hour treatment. A tissue microarray analysis of 109 primary tumour biopsies revealed a subset of patients (20-23%) with intact Rb, but defective p16 or overexpression of CDK4 and/or CDK6. These patients might benefit from CDK4/CDK6 inhibition, therefore our results are promising and might be translated to the clinic.

Our data strongly support investigation of palbociclib in combination with venetoclax as an innovative treatment strategy for chemoresistant MCL patients without RB1 deletion.

KSHV infected SH-SY5Y cells and promoted the cell proliferation. KSHV infection increased the expression of Notch signaling pathway proteins, which may have been associated with the enhanced cell proliferation.

No methylation was observed in the normoxia-exposed group. These observations suggested that p16 loss may stimulate aberrant LF proliferation via the p16/cyclin D1/CDK4/Rb/E2F1 pathway.

In order to elucidate the effect of CDK4 on drug sensitivity, CDK4‑overexpressing OS cell lines were treated with cisplatin (CDDP); significant attenuation of CDDP sensitivity, demonstrated by increased cell viability and decreased expression of cleaved caspase‑9, was induced by enforced expression of CDK4. In addition, treatment with CDK4/6 inhibitor palbociclib in CDK4‑overexpressing U2OS cells facilitated apoptosis and a significant decrease in cell viability in a dose‑dependent manner. In conclusion, the results of the present study showed that higher expression and amplification of CDK4 in tumors is a predictive biomarker for resistance to conventional chemotherapy in patients with OS and that palbociclib is a promising drug for this therapeutically challenging cohort.

The present results indicated that miR‑198 suppressed OSCC tumour growth and metastasis by directly targeting CDK4 expression. Thus, miR‑198 may be a potential therapeutic target in the treatment of OSCC.

The expression and prognostic values of AURKA and RB1 may also be significant to CRC diagnosis. CDKs together with the co-expressed genes and their association with immune infiltrates may serve as target molecules for immunotherapy in CRC.