Non-Genetic Mechanisms of Fractional Resistance to Abemaciclib in Dedifferentiated Liposarcoma.

Dedifferentiated liposarcoma is a rare mesenchymal malignancy driven by amplification of chromosome 12q13-15, which includes the oncogenes CDK4 and MDM2. CDK4 amplification provides a rationale for targeted therapy with CDK4/6 inhibitors, and abemaciclib has shown the most durable activity reported to date in this disease. Clinical responses, however, are incomplete and often transient, and the cellular features that allow tumor cells to continue proliferating during treatment are not well understood. To address this gap, we performed multiplexed single-cell imaging to quantify 17 cell-cycle regulators in both dedifferentiated liposarcoma cell line Lipo246 and surgically resected primary human cells exposed to abemaciclib. Both models contained a subpopulation of cells that retained phosphorylated retinoblastoma protein, a marker of cell proliferation, at the highest abemaciclib doses. These fractionally resistant cells were defined by selective enrichment of cyclin-dependent kinase 2 (CDK2), cyclin B1, and phosphorylated ribosomal protein S6 (pS6), and showed enhanced sensitivity to the CDK2 inhibitor, tagtociclib. Together, these findings reveal nongenetic cell cycle plasticity as a mechanism of escape from CDK4/6 inhibition in dedifferentiated liposarcoma and nominate CDK2 and the PI3K-mTOR pathway as candidate targets for combination therapy.