The five year survival rate for pancreatic ductal adenocarcinomas (PDAC) is approximately 5% making it one of the most lethal cancers in the United States. Despite the fact that more than 90% of PDAC contain activating mutations within the gene encoding the GTPase KRas, the development of small-molecule inhibitors for KRas has only been successful for the G12C allele accounting for 3% of KRAS mutations in PDAC. As such, inhibiting pathways which are essential for KRas-driven transformation and tumorigenesis may provide a more promising avenue for the development of PDAC targeted therapies. One such pathway that is upregulated in response to oncogenic KRas expression encompasses a set of catabolic processes termed autophagy. Indeed, a wealth of indicative publications suggest that autophagy could represent an Achilles’ heel for certain aggressive and intractable cancers, and inhibitors that globally block autophagy have shown some promise in cell culture and mouse models of PDAC. However, therapeutic concentrations of these autophagy inhibitors resulted in toxicity. Further translational progress has been hampered by the lack of specific reagents: autophagy is actually not a single process but rather a broad family of pathways with distinct cargo preferences and mechanisms of recruitment. Recently, oncogenic KRasG12V expression, which accounts for 30% of KRAS mutations in PDAC, has been shown to result in the upregulation of a specialized form of autophagy, termed mitophagy, in which specific mitophagy receptors mark mitochondria for degradation. The goal of this proposal is to determine the role of mitophagy in KRasG12V transformation and PDAC. Our central hypothesis is that KRas dysregulation leads to the upregulation of mitophagy to promote neoplastic transformation. To test this hypothesis we have developed two specific aims. Aim 1 will determine which of the known mitophagy receptors are required for KRasG12V transformation. Furthermore, in mammalian cells, many of these pathways are redundant, preventing facile dissection in transformed cells. Aim 2 will leverage a novel combination of structural and genetic approaches to identify novel mitophagy receptors and cognate interaction partners and thus explore mechanisms of mitophagy in Ras-dysregulated