Dataset Information

The Role of CDK4 in the Pathogenesis of Pancreatic Cancer.

ABSTRACT: Pancreatic cancer (PC) continues to have the lowest overall survival and the lack of effective early diagnosis. Cyclin-dependent kinase 4 (CDK4) plays a fundamental role in the orderly progression of the cell cycle, binding to cyclin D to promote the progression through the G1/2 transition. The inhibition of CDK4/6 has therefore gained substantial interest in the hope of new and effective therapeutics in multiple cancers, such as advanced metastatic breast cancer. While the use of these agents is encouraging, their potential is yet to be fully explored. In this study we used the GLOBOCAN database to understand the most recent epidemiology of PC, Human Protein Atlas and KEGG to highlight the role, prevalence, and significance on patient survival of CDK4 in PC. We found that CDK4 cannot be used as prognostic in PC and no significant differences were observed between CDK4 expression and the patient's clinical status, though larger studies, especially concerning CDK4 protein expressions, are required for a more thorough understanding. The use of CDK4/6 inhibitors in PC is still in clinical trials. However, due to only modest improvements observed in the use of single-agent therapies, efforts have focused on combinatorial approaches.

SUBMITTER: Jiggens E

PROVIDER: S-EPMC8620733 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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The Role of CDK4 in the Pathogenesis of Pancreatic Cancer.

Jiggens Emily E Mortoglou Maria M Grant Guy H GH Uysal-Onganer Pinar P

Healthcare (Basel, Switzerland) 20211030 11

Pancreatic cancer (PC) continues to have the lowest overall survival and the lack of effective early diagnosis. Cyclin-dependent kinase 4 (CDK4) plays a fundamental role in the orderly progression of the cell cycle, binding to cyclin D to promote the progression through the G1/2 transition. The inhibition of CDK4/6 has therefore gained substantial interest in the hope of new and effective therapeutics in multiple cancers, such as advanced metastatic breast cancer. While the use of these agents i ...[more]

PMID: 34828525

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Project description:Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK-MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As inhibition of other proteins might also counter CDK4/6i-mediated signaling changes to increase cellular CDK4/6i sensitivity, a CRISPR-Cas9 loss-of-function screen was conducted that revealed a spectrum of functionally diverse genes whose loss enhanced CDK4/6i growth inhibitory activity. These genes were enriched around diverse signaling nodes, including cell-cycle regulatory proteins centered on CDK2 activation, PI3K-AKT-mTOR signaling, SRC family kinases, HDAC proteins, autophagy-activating pathways, chromosome regulation and maintenance, and DNA damage and repair pathways. Novel therapeutic combinations were validated using siRNA and small-molecule inhibitor-based approaches. In addition, genes whose loss imparts a survival advantage were identified (e.g., RB1, PTEN, FBXW7), suggesting possible resistance mechanisms to CDK4/6 inhibition. In summary, this study has identified novel combinations with CDK4/6i that may have clinical benefit to patients with PDAC.SignificanceCRISPR-Cas9 screening and protein activity mapping reveal combinations that increase potency of CDK4/6 inhibitors and overcome drug-induced compensations in pancreatic cancer.

Dataset Information

The Role of CDK4 in the Pathogenesis of Pancreatic Cancer.

Publications

The Role of CDK4 in the Pathogenesis of Pancreatic Cancer.

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