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Characterization of esophageal squamous cell carcinoma cell lines sensitivity to Palbociclib

ABSTRACT: Background: Esophageal squamous cell carcinoma (eSCC) is a highly aggressive malignancy with poor prognosis and limited therapeutic options. Although immune checkpoint inhibitors such as nivolumab, have shown clinical benefit, particularly in patients with high PD-L1 expression, this subgroup represents only a small fraction of eSCC cases. CDK4/6 inhibitors such as palbociclib have only been tested as second-line agents in eSCC, often in combination with EGFR inhibitors, with minimal benefit. Methods: Our study evaluates palbociclib as a first-line therapy in treatment-naive eSCC models. Using a panel of 22 eSCC cell lines with integrated multi-omics and phenotypic assays. Results: We identified three response subtypes, resistant, delayed and arrested, correlated to Rb-pathway status. Interestingly, in delayed responders, palbociclib induced replication stress, DNA damage, and unprotected micronuclei enriched for cGAS, triggering activation of interferon-stimulated genes. Consistent with this, palbociclib enhanced immune cell infiltration in delayed eSCC spheroids within a preclinical vascularized 3D microfluidic system. Conclusions: Our study demonstrates that first-line palbociclib treatment unmasks intrinsic vulnerabilities in the CDK4/6-Rb axis and triggers innate immune activation in molecularly defined eSCC. Using a translationally relevant 3D vascularized microfluidic system, we provide evidence that early CDK4/6 inhibition not only stall cancer cell growth but also promotes immune cells recruitment. In conclusion, our study identifies palbociclib as a viable first-line therapeutic candidate in selected eSCC patients and uncover its immunomodulatory potential. These findings support further research into CDK4/6 inhibition as first-line treatment for eSCC and highlight its potential to influence the tumor immune microenvironment in ways that could improve responses to combination therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE312063 | GEO | 2026/02/02

REPOSITORIES: GEO

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Project description:Osteosarcoma (OS) is the most common primary bone cancer in adolescents, young adults (AYA), and children, with up to 25% of patients developing metastatic disease, primarily in the lungs. Despite survival rates being >70% for localized tumors, patients with metastatic OS have <30% survival due to limited effective salvage therapies. OS is characterized by chromosomal instability (CINs) and dysregulated CDK4/6 and PI3K/mTOR pathways. The retinoblastoma protein (RB), a downstream target of CDK4/6, is a key regulator of G1/S cell cycle progression. We validated these targets in OS cell lines, xenografts, and patient-derived xenografts (PDXs), revealing CDK4/6 hyperactivation. While CDK4/6 inhibitors show promise, they are ineffective as monotherapies due to cytostatic effects and resistance from compensatory pathways, such as PI3K/AKT/mTOR. This study investigates dual inhibition of CDK4/6 and PI3K/mTOR using palbociclib and voxtalisib, respectively, in OS models. In RB proficient (RB+) OS lines, the combination therapy exhibited synergistic inhibition of cell growth and G1 arrest, while inducing autophagy without disrupting palbociclib-induced senescence. Prolonged treatment triggered autophagy in treatment-naïve PDXs, with senescence partially reversed in the combination group. Combination therapy enhanced palbociclib efficacy in both pretreated and naïve PDX models, improving survival. Mechanistically, palbociclib reduced CDK1/2 activity, while voxtalisib suppressed CDK1/2 and RB1 phosphorylation, impairing cell cycle progression. The combination significantly reduced metastatic burden and improved survival in OS lung colonization models, inhibiting pre-established metastatic foci. Kinome profiling and proteomic analyses confirmed decreased PI3K and mTOR activity. This study highlights the potential of CDK4/6 and PI3K/mTOR dual inhibition in OS, offering therapeutic promise for overcoming resistance and improving outcomes in pediatric and AYA patients with CDK4/6 hyperactivation.

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Characterization of esophageal squamous cell carcinoma cell lines sensitivity to Palbociclib

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