Abstract

A reprogrammed transcriptional state is required for malignant transformation, a process that can render cancer cells addicted to specific transcriptional regulators. Our research focuses on identifying transcriptional addictions in cancer using genetic screens, followed by a deep investigation of underlying mechanisms. Over several years, our studies have reinforced the role of sequence-specific DNA binding transcription factors as the premier transcriptional addictions deserving of therapeutic intervention, such as MYB in acute myeloid leukemia and POU2F3 in small cell lung cancer. However, such targets are among the most challenging to target directly with small-molecules, which has motivated our efforts to study how TF oncoproteins interact with their cofactors, such BRD4 , p300, TFIID , and Mediator. My presentation will discuss two of our recently identified transcriptional addictions in cancer identified via genetic screens and our efforts aimed at revealing properties that distinguish effective from ineffective transcriptional therapies.