Christopher Vakoc Lab

Cancer cells depend on molecular programs that sustain their growth, survival and identity. Some of these dependencies arise from cancer-causing mutations; others reflect the developmental programs of the tissues from which tumors originate. Our laboratory seeks to understand these vulnerabilities and determine how to exploit them therapeutically while preserving normal tissue function.

We combine functional genomics, biochemistry and chemical biology to discover cancer dependencies and uncover the mechanisms that make them essential. A central focus is the machinery that controls gene expression: transcription factors, chromatin regulators and the signaling pathways that govern their activity. Our goal is to translate a detailed understanding of cancer biology into more effective treatments, with a growing emphasis on childhood leukemias and solid tumors.

Why does a protein become essential in one cancer but remain dispensable in another? Answering this question can reveal opportunities for selective therapy. We have used genetic screens to identify cancer dependencies, then investigated how these proteins function and why particular tumors rely on them. By connecting molecular mechanism with therapeutic response, we aim to establish both how a target can be attacked and which cancers are most likely to respond.

Our work identified the chromatin regulator BRD4 as a dependency in acute myeloid leukemia and demonstrated the therapeutic potential of BET bromodomain inhibition. This discovery helped establish a foundation for developing drugs that target the machinery controlling cancer gene expression. We have since expanded our studies to diverse transcriptional regulators, chromatin-associated enzymes and signaling proteins that sustain malignant cell states.

Our laboratory also identified a tuft-cell-like subtype of small cell lung cancer defined by the transcription factor POU2F3. This work revealed how a normal developmental program can be repurposed to sustain an aggressive malignancy. By dissecting the transcription factors and coactivators that maintain this cancer’s identity, we are uncovering vulnerabilities that could support new therapeutic approaches.

Across these projects, we seek to move beyond identifying proteins that cancer cells need. We investigate which molecular functions must be disrupted to produce a durable response — and whether doing so can trigger cell death, promote differentiation or prevent cancer cells from recovering after treatment. These studies guide our efforts to turn biological discoveries into therapeutic strategies.

New approaches are essential for discovering cancer vulnerabilities and understanding how to target them. Our laboratory pioneered domain-focused CRISPR-Cas9 screening and CRISPR exon scanning to map functionally important regions within cancer-relevant proteins. These methods allow us to examine dependencies at the level of individual protein domains and connect specific molecular functions to cancer cell fitness. We integrate these tools with epigenomics, biochemical and structural studies, chemical biology and disease models. Together, these approaches help us distinguish the functions that sustain cancer from those required by normal cells and prioritize opportunities for therapeutic development.