ABSTRACT Mucinous neoplasms of the appendix (MNA) are rare tumors that may progress from benign to malignant disease and ultimately assume an aggressive biological behavior. The metastatic tumor cells often secrete large quantities of mucin resulting in the clinical syndrome known as pseudomyxoma peritonei (PMP), the vast majority of which originates from the appendix. Once peritoneal metastasis has occurred, disease progression is frequently fatal, often with massive accumulation of tumor masses and mucin that can fill the abdominal cavity, resulting in death from intestinal obstruction and cancer cachexia. While the primary treatment of PMP is surgical, patients with higher-grade mucinous cancers and those with inoperable disease typically receive cytotoxic therapies approved for colorectal cancer (CRC), which generally have limited efficacy. New approaches are clearly needed to elucidate the underlying biology of PMP and to develop new and more effective targeted treatment strategies. Discoveries by the Lowy lab revealed the mutational landscape of PMP (Genome Med. 2014), which is characterized by pathogenic alterations in the KRAS and GNAS oncogenes. The latter has been the focus of the Gutkind lab for many years, who pioneered the study of G proteins in cancer (Nature Rev. Cancer 2010, 2013). Recently our collaborative work has suggested that MNA may be exquisitely sensitive to inhibition of cyclin dependent kinase (CDK) 4/6. Our preliminary data includes treatment of a patient with mucinous carcinomatosis-low grade of appendiceal origin whose disease progressed on standard of care chemotherapy, but who has had stable disease for greater than 6 years on single agent Palbociclib, the first FDA-approved CDK4/6 inhibitor. Recently we have developed further evidence that this sensitivity to CDK4/6 inhibition, may in fact be related to the activation of PKA signaling downstream of GNAS and therefore, we hypothesize that GNAS mutant tumors of the appendix and colon and possibly those of other histology’s (ie- pancreas) may be sensitive to this targeted therapy as well. In this proposal, we will test this hypothesis, explore how CDK4/6 inhibition may modulate the tumor microenvironment to control GNAS mutant tumor progression and explore the underlying mechanisms underpinning this sensitivity.