Small cell lung cancer (SCLC) remains lethal, with a ~5% long-term survival rate. Smoking, advanced age, and bi-allelic mutations in TP53 and RB1 are commonly associated to SCLC. We will decipher the existence of epigenetic heterogeneity of SCLC and its actionability in patient-derived xenograft models by mapping and targeting G-quadruplex (G4) DNA structure formation. To re-sensitize chemo-resistant SCLC, we will systematically interfere with the activity of critical transcription factors, regulators, and G4 DNA in vivo. Taken together, our investigations will reveal novel aspects of SCLC biology and establish a proof-of-principle framework to diagnose and treat chemo-naïve and -resistant SCLC.