Mutationally activated KRAS comprises the major oncogenic driver in the top three causes of cancer deaths in
the US: lung (LAC), colorectal (CRC), and pancreatic ductal adenocarcinoma (PDAC). In 2021, a milestone in
anti-KRAS drug discovery was achieved, with the first clinically effective direct inhibitor of KRAS approved, for
the treatment of KRASG12C mutant lung cancer. However, as with essentially all targeted anti-cancer therapies,
both de novo resistance and treatment-associated acquired resistance have recently been reported. As
anticipated, mutations that reactivate RAS and RAS effector signaling through the RAF-MEK-ERK mitogen-
activated protein kinase signaling network (e.g., activating mutations in BRAF, MEK1) were identified in LAC and
CRC patients treated with KRASG12C selective inhibitors (G12Ci), and combinations that concurrently target these
resistance mechanisms are now under clinical evaluation. However, no genetic mechanisms were identified in
up to 50% of patients who relapsed on G12Ci treatment. To address possible ERK MAPK-independent
resistance mechanisms, my studies have identified and validated the downstream target of the Hippo tumor
suppressor pathway, the YAP1 transcriptional coactivator and oncoprotein, as a driver of resistance to G12Ci-
mediated growth suppression. Consistent with previous studies that established the ability of YAP1 activation to
overcome addiction to mutant KRAS, my preliminary analyses demonstrated that ectopic overexpression of wild-
type or activated YAP1 drives resistance to G12Ci treatment in KRASG12C mutant LAC, CRC and PDAC cell
lines. This finding establishes the rationale and foundation for my research goal: to determine the mechanistic
basis for YAP1-mediated resistance to G12Ci treatment. I hypothesize that identification of YAP1-driven
resistance mechanisms will establish combinations of pharmacologic inhibitors that can enhance the
long-term anti-tumor efficacy of G12Ci and other KRAS-targeted therapies. I have developed three aims to
address the mechanisms by which YAP1 drives resistance. First, I will determine the role of the TEAD
transcription factors in YAP1-driven KRAS-independence. These studies may validate the clinical application of
TEAD inhibitors for the treatment of KRAS-mutant PDAC and other cancers. Second, I will identify YAP1-
regulated genes that sustain KRAS-independent growth, in support of a model where YAP1 overcomes KRAS-
addiction by restoring expression of key KRAS-regulated genes. Finally, I will identify KRAS-regulated metabolic
processes that are both sustained by YAP1 activation and important for PDAC growth. Taken together, my
studies may validate an important driver of resistance to all KRAS-targeted therapies and define therapeutic
approaches to overcome YAP1-driven drug resistance. These studies will require my application of a diverse
spectrum of experimental approaches, advance my understanding of key steps in anti-cancer drug development,
and foster my career development as an independent cancer researcher.