mTOR activity promotes cell cycle re-entry following CDK4/6 inhibitor-mediated G1 arrest in T leukaemic cells
Dynamic cell signaling responses enable cells to respond to changing extracellular stimuli. In cancer, this plasticity can be used by transformed cells to rapidly develop resistance to chemotherapy. Small molecule inhibitors of cyclin-dependent kinases 4/6 inhibition are standard-of-care treatment for metastatic breast cancer. It will be important to establish efficacy and mechanisms of resistance to these inhibitors in other cancer types. In this study, we have characterized the effects of CDK4/6 inhibition in T acute lymphocytic leukemia (T-ALL), a malignancy characterized by high Cyclin D3 expression and aberrant Notch signaling, using the model Jurkat T cell line. We demonstrate that short-term treatment with the CDK4/6 inhibitor palbociclib (PD) potently arrests cells in G1, but these cells subsequently re-enter the cell cycle. Mechanistically, we show that cell cycle re-entry is unlikely driven by c-Myc, unlike in breast cancer cells. Instead, PD treatment induces a transient suppression of mTOR signaling, which is reactivated to promote cell enlargement, cell signaling rewiring and cell cycle re-entry. Our results highlight the importance of non-mutational alterations in gene expression and signaling programs in cancer cells to resist proliferation cessation.