Pancreatic adenocarcinoma (PDAC) remains a therapeutic challenge, making the identification of new targets
and development of novel treatment strategies for this disease of paramount importance. Our LONG-TERM
GOAL is to advance context-dependent, mechanism-based paradigms for the improved use of epigenomic
inhibitors in cancer. Epigenomic machinery, and hence their inhibitors, are typically only considered within the
context of their actions in gene expression, or interphase, even though they are operational during different
stages of the cell cycle. During the process of DNA replication, for instance, not only is the entire genome
replicated, but the accompanying chromatin structure is duplicated as well. Thus, conceptually, DNA
replication represents a vulnerable moment for challenging genomic and epigenomic integrity, which relies
heavily on the proper functioning of the S-phase DNA replication checkpoint (DRC) and DNA damage
response (DDR) as critical components of this process. Early in tumorigenesis, higher proliferation rates
driven by activated oncogenes, such as KRAS, trigger replication stress (RS), which if not tolerated causes
cell senescence or death. RS tolerance, consequently, becomes vital to tumor progression, yet the underlying
mechanisms remain poorly understood. Here, we will test the CENTRAL HYPOTHESIS that the epigenomic
regulator G9a promotes RS tolerance in PDAC via a mechanism which involves interactions with S-phase
DRC-DDR pathways, representing actionable vulnerabilities for therapeutics. Completion of these studies will
significantly advance the field by: 1. revealing mechanisms by which G9a functions in the tolerance to
oncogene-induced RS, a key understudied event in tumorigenesis, 2. providing novel mechanistic insight into
how G9a-mediated function in DDR signaling protects replication fork integrity to offer additional targeting
strategies for the subset of patients with inherent DDR deficiencies, and 3. leveraging the function of
epigenetic regulators during oncogene-driven RS as a mechanistic opportunity to synergize with RS-
enhancing drugs, such as DDR-inhibitors. In summary, we seek to extend our studies on new mechanisms
that represent previously unrecognized actionable vulnerabilities for cancer cells. We are optimistic that the
outcome of this research will impact planning for future clinical testing of therapies that may share similar
mechanisms to offer much-needed, novel treatments for PDAC.