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Targeting LPAR4 overcomes stress adaptation to CDK4/6 inhibition in soft tissue sarcoma [RNAseq]

ABSTRACT: CDK4/6 inhibitors are under active clinical evaluation in sarcoma, yet the mechanisms governing sensitivity and resistance remain unclear. We show that the CDK4/6 inhibitor abemaciclib not only suppresses tumor cell proliferation but also induces robust type I interferon signaling driven by dsRNA accumulation, which is essential for its anti-tumor activity. Abemaciclib reshapes the sarcoma immune microenvironment by increasing T cell infiltration and enhancing intratumoral interferon-producing monocytes. Integrated transcriptomic and proteomic analyses identified Lysophosphatidic Acid Receptor 4 (LPAR4) as an adaptive stress-response factor upregulated in tumor cells upon treatment and associated with poor patient prognosis. Functionally, LPAR4 mitigates interferon-induced mitochondrial stress, limiting reactive oxygen species accumulation and apoptosis, while its silencing exacerbates mitochondrial dysfunction and promotes tumor cell death. In vivo, LPAR4 loss synergizes with abemaciclib to inhibit tumor growth and prolong survival. These findings establish LPAR4 as a key regulator of stress adaptation and a promising target to potentiate CDK4/6-based therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE313214 | GEO | 2026/04/01

REPOSITORIES: GEO

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Project description:Background: Few druggable targets have been discovered in glioblastoma (GBM); however, increasing knowledge has uncovered two hallmarks of this disease: epigenetic modifications and cell cycle dysregulation. Methods: Here, we investigated the effects of the EZH2 inhibitor GSK126 alone and in combination with the CDK4/6 inhibitor abemaciclib on morphology, growth, invasiveness, protein and gene expression, mitochondrial function, and induction of cell death in patient-derived GBM cells (GBM03, GBM06, GBM14, and GBM15). Results: EZH2 expression, CDK4 amplification, and CDKN2A deletion were first confirmed. The combined use of GSK126 and abemaciclib resulted in synergistic effects in all patient-derived GBM cell lines. After treatment, the cells appeared swollen with a large flat cytoplasm and cellular stress fibers due to HIF1 upregulation and CalR translocation. Notably, abemaciclib-induced cellular stemness (NANOG+, OCT3/4+, and SOX2+) was antagonized by this combination treatment. The MitoStress Test revealed a massive impairment of mitochondrial function. The basal oxygen consumption rate, ATP synthesis, and maximal respiration of the mitochondria decreased, confirming reduced cellular fitness and disrupted endoplasmic reticulum-mitochondrial homeostasis. This was paralleled by massive mitochondrial ROS production leading to mitochondrial depolarization and upregulation of the UPR sensors PERK, ATF6, and IRE1. Spheroid invasion was reduced in 3/4 cases, again with synergistic effects after dual EZH2 and CDK4/6 blockade. Differentially expressed genes involved mitotic aberrations/spindle assembly (Rb, PLK1, RRM2, PRC1, CENPF, TPX2), histone modification (HIST1H1B, HIST1H3G), DNA damage/replication stress events (TOP2A, ATF4), immuno-oncology (DEPDC1), and a shift in the stemness profile towards a more differentiated state. Notably, the antitumor effect was partially confirmed in ovo as well as in patient-derived organoids. Conclusions: We propose dual blocking of GBM hallmarks as a potential treatment strategy. Biomarker-driven targeted therapies will hopefully guide the development of more refined treatments.

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Targeting LPAR4 overcomes stress adaptation to CDK4/6 inhibition in soft tissue sarcoma [RNAseq]

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