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

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.