Abstract
Drugs targeting the cyclin-dependent kinase 4/6 (CDK4/6)–retinoblastoma 1 (RB1) axis have shown efficacy against multiple solid cancers, but their therapeutic potential in pancreatic cancer remains poorly defined. A recent report proposed that a “tailored” combination of first-line and second-line CDK4-targeting drugs would hold promise for pancreatic cancer treatment. Indeed, this therapeutic strategy exhibited significantly suppressive effects on pancreatic cancer patient-derived cell lines and tumor tissue in vitro. However, the study neglected immune involvement and the influence of CDK6 and RB1 in CDK4 inhibition-based treatment. Herein, we reveal multiple new facets of the CDK4/6–RB1 axis in pancreatic cancer, highlighting the complexity of this signaling axis for future prognostic and therapeutic targeting.
Highlights
Pancreatic ductal adenocarcinoma (PDA) is the most prevalent pathohistological type of pancreatic cancer and is characterized by high lethality rates (Kleeff et al, 2016)
To determine the immunologic relevance of CDK4 in pancreatic cancer, we integrated all relevant datasets in the The Cancer Genome Atlas (TCGA) database for bioinformatics analyses
In pancreatic adenocarcinoma (PAAD), the results showed a positive correlation between CDK4 and the immunomodulatory system, including the immune effector molecules PRF1, GZMB, and IFNG (Figures 1A–C), as well as immune cells (Figures 1D–I)
Summary
Pancreatic ductal adenocarcinoma (PDA) is the most prevalent pathohistological type of pancreatic cancer and is characterized by high lethality rates (Kleeff et al, 2016). Mutations in multiple tumor suppressor genes contribute to the tumorigenesis and progression of PDA, including but not limited to CDKN2A (Collisson et al, 2019). As a Polycomb repressed cell cycle checkpoint gene, CDKN2A encodes P16INK4A that binds to cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) to prevent retinoblastoma 1 (RB1) phosphorylation (Rubin, 2013). Chou et al (2018) reported a “tailored” combination of first-line and second-line CDK4-targeting drugs for PDA therapy, guided by the predictive marker RB1. This strategy showed translational potential, genomic analyses suggest that the conventional CDK4/6–RB1 signaling pathway is divergent in pancreatic cancer, questioning the efficacy of this therapy
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