Hangauer Research Group
The Hangauer lab at UC San Diego studies the process by which initially drug sensitive tumors become drug resistant. Acquired resistance occurs during treatment with targeted therapies, chemotherapies, radiation, and immunotherapy. This process prevents effective therapies from achieving durable responses or cures. While factors including drug resistance-conferring mutations, tumor cell state transitions and immune suppression are understood to contribute to acquired resistance, the molecular details remain to be determined. Current strategies to combat acquired resistance include combinatorial or sequential treatments, but these approaches rarely provide long term responses. We propose that there are yet to be discovered gene-driven processes which are necessary for acquired resistance. By uncovering the molecular mechanisms of key events such as drug stress-induced mutagenesis, survival of CD8 T cell attack, and suppression of apoptosis, we seek to identify novel therapeutic targets to prevent acquired resistance.
Our lab focuses on understanding these mechanisms within the residual cancer cells that survive initial treatment and seed tumor recurrence. These "persister" cells enter a quiescent, pro-survival cell state and avoid drug-induced cell death. Persister cells, also known as minimal residual disease, have been reported in every solid tumor type tested thus far with both targeted therapies and chemotherapies. The distinguishing feature of persister cell biology is an initially reversible drug tolerance demonstrated by resensitization to drug treatment following a period of drug-free regrowth. This reversibility indicates that initial persister cell drug tolerance is not based on irreversible genetic mutations:
We have also observed persister cells which survive immunotherapy and radiation. For example, human melanoma persister cells reversibly survive prolonged exposure to primary human CD8 T cells engineered to recognize a tumor antigen (TCR T cells):
Importantly, upon extended exposure to treatment, a subset of persister cells regrow into resistant colonies termed "expanded persister" cell colonies harboring drug resistance-conferring mutations not found prior to treatment. We have observed expanded persister cells colonies with both targeted therapies and immunotherapy:
We previously discovered that persister cells are vulnerable to death by ferroptosis rather than apoptosis (Hangauer et al., Nature 2017). Targeting GPX4 to selectively induce ferroptotic death in persister cells is a promising therapeutic approach to prevent acquired resistance. Current projects are focused on understanding GPX4 and other persister cell gene vulnerabilities, determining how drug resistance-conferring mutations arise during treatment, and exploring the relationship between persister cells which survive distinct treatment modalities. We utilize techniques including scRNAseq, CRISPR and chemical screening to generate hypotheses which we test in novel models of acquired resistance. Ultimately, we seek to translate our findings into therapeutic approaches that will benefit cancer patients.