TIAM1-RAC1 Promote Survival of Small Cell Lung Cancer Cells Through Antagonizing Nur77-Induced BCL2 Conformational Change

Small cell lung cancer (SCLC), an aggressive neuroendocrine malignancy, has limited treatment options beyond platinum-based chemotherapy, whereafter acquired resistance is rapid and common. By analysing expression data from SCLC tumours, patient-derived models and established cell lines, we discovered that expression of TIAM1, an activator of the small GTPase RAC1, is associated with a neuroendocrine gene program. TIAM1 depletion or RAC1 inhibition reduced viability and tumorigenicity of SCLC cells by increasing apoptosis associated with conversion of BCL2 from its pro-survival to pro-apoptotic function via BH3 domain exposure. This conversion depended upon cytoplasmic translocation of Nur77, an orphan nuclear receptor. TIAM1 interacts with and sequesters Nur77 in SCLC cell nuclei and TIAM1 depletion or RAC1 inhibition promoted Nur77 translocation to the cytoplasm. Mutant TIAM1 with reduced Nur77 binding failed to suppress apoptosis provoked by TIAM1 depletion. In conclusion, TIAM1-RAC1 signalling is required for SCLC cell survival via nuclear sequestration of Nur77.