The research interests of the laboratory of Janet Houghton focus on new target identification, development of novel small molecule inhibitors of critical targets, mechanisms of drug action, drug resistance, and translational therapeutics spanning basic research to clinical trials. Her lab researches the critical role of the transcription factor GLI in the survival of colon cancer cells and other cancers that constitutively express GLI and mutant KRAS genes. This involves determining mechanisms by which small molecule inhibitors of GLI induce extensive cell death by inhibiting GLI-dependent transcription and shutting off this signaling program. Mechanisms focus on the impact of GLI on transcriptional regulation, R-loop formation, and the initiation of DNA replication licensing in promoter regions. Her research over more than three decades has contributed significantly to our understanding of the mechanism of action of 5-fluorouracil and the role of leucovorin in colon cancer, how death receptor signaling regulated by members of the TNF receptor superfamily impacts cell death in cancers, and subsequently GLI as a therapeutic target for drug discovery in cancer.