Hangauer Lab Research Focus
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 and is arguably the predominant cause of patient mortality. 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 (minimal residual disease) and seed tumor recurrence. These "persister" cells enter a quiescent, pro-survival cell state and avoid drug-induced cell death. Persister cells have been reported in every solid tumor type tested thus far. 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 (bottom left images below). This reversibility indicates that initial persister cell drug tolerance is not based on irreversible genetic mutations:
Importantly, upon extended exposure to treatment, a subset of persister cells regrow into resistant colonies termed "expanded persister" cell colonies (top right image above). Once persister cells begin to regrow they are thought to contain drug resistance-conferring mutations which did not preexist. Indeed, recent reports indicate that by this stage, there are multiple parallel genetically-driven resistant mechanisms present within the same tumor cell population. If this is the case, it may be impossible to effectively treat tumors which have already passed through this process and have regrown because therapeutic targeting of numerous distinct mechanisms of resistance is not practical due to toxicities associated with co-treating patients with multiple drugs. Therefore, it may be critical to eliminate persister cells prior to their initial regrowth in order to prevent acquired resistance. Toward this goal, 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 in the lab are focused on identifying and understanding persister cell vulnerabilities including GPX4, determining how drug resistance-conferring mutations arise in persister cells and whether this can be prevented, and interrogating persister cells which survive immune cell attack and may contribute to acquired resistance to immunotherapy. To explore these questions, we utilize techniques including scRNAseq, CRISPR and chemical screening together with novel models of acquired resistance. Ultimately, we seek to translate our findings into therapeutic approaches that will benefit cancer patients.