Understanding Treatment Resistance and Residual Disease in Pancreatic Adenocarcinoma
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gong-dgong3-phd-hst-2026-thesis.pdf
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Author(s)
Gong, Dennis H.
Advisor(s)
Hwang, William L.
Date Issued
May 2026
Publisher
Massachusetts Institute of Technology
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one the most aggressive, treatment resistant, and deadliest cancer types. Multiagent chemotherapy is currently the standard of care, but recently KRAS inhibitors, which target gain of function KRAS mutations in >95% of PDAC patients, have entered clinical trials and reported unprecedented improvements in response rates and overall survival. Still, PDAC tumors continue to eventually resist both broad cytotoxic chemotherapy and KRAS targeted regimens, leaving surgery as the only curative treatment modality for the minority patients who are eligible. However, even surgery leaves traces of residual disease, and
recurrence occurs in roughly 80% of patients. This dissertation uses multi-modal tools and diverse experimental approaches to characterize, understand, and target the biology of treatment resistant and residual disease. First, I develop and apply new methods to integrate morphological profiling with molecular characterization across many patient derived cell lines, revealing treatment induced effects on cancer cell state. Next, I perform detailed spatial and multi-omic characterization of a neural-like progenitor cell state, which is enriched in residual disease in patient tumors. Finally, I perform unbiased transcription factor overexpression screens to identify genetic factors that enable treatment resistance. Altogether, we identify and characterize new mechanisms of treatment resistance and persistence in residual disease, motivating therapeutic strategies for this deadly disease.
MIT Department
Harvard-MIT Program in Health Sciences and Technology
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