Supplementary Figure S2 from Separable Cell Cycle Arrest and Immune Response Elicited through Pharmacological CDK4/6 and MEK Inhibition in RAS^mut Disease Models

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posted on 2024-12-03, 08:22 authored by Jin Wu, Jianxin Wang, Thomas N. O’Connor, Stephanie L. Tzetzo, Katerina V. Gurova, Erik S. Knudsen, Agnieszka K. Witkiewicz

Supplementary Figure S2. A. Immunofluorescent analysis of RB expression in HT1080-sgCtrl and sgRB cells. Scale bar = 50 μm. B. Relative mouse body mass for each cohort. HT1080-sgCtrl-vehicle (n = 4), HT1080-sgCtrl-CDK4/6i + MEKi (palbociclib (100 mg/kg) + trametinib (0.5 mg/kg), n = 4), HT1080-sgRB-vehicle (n = 4), HT1080-sgRB- CDK4/6i + MEKi (palbociclib (100 mg/kg) + trametinib (0.5 mg/kg), n = 3). C. Excised tumor representative images from each cohort following the final treatment. Scale bar = 1 cm. D. Violin plot displaying tumor mass from each cohort plotted as mean ± SD. **p < 0.01, ***p < 0.001 as determined by two-way ANOVA.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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ARTICLE ABSTRACT

The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth. CRISPR-mediated RB1 depletion resulted in a decreased response to CDK4/6 and MEK inhibition, which was validated in both cell culture and xenograft models. Beyond its cell cycle inhibitory effects, pathway enrichment analysis revealed the robust activation of interferon pathways upon CDK4/6 and MEK inhibition. This induction of gene expression was associated with the upregulation of retroviral elements. The TANK-binding kinase 1 inhibitor GSK8612 selectively blocked the induction of interferon-related genes induced by palbociclib and trametinib treatment and highlighted the separable epigenetic responses elicited by combined CDK4/6 and MEK inhibition. Together, these findings provide key mechanistic insights into the therapeutic potential of CDK4/6 and MEK inhibition in soft tissue sarcomas.