Skip to main content
Presentation Time: 4:00-4:20
Home University: UNC-Chapel Hill
Research Mentor: Channing Der, Ph.D., Pharmacology
Program: CSF
Research Title: Defining the Role of Mitochondrial Dynamics in Regulating PDAC Cell Sensitivity to ERK Inhibition

Pancreatic ductal adenocarcinoma (PDAC) is driven by oncogenic activation of KRAS in over 95% of patients. Recent evidence suggests that mutant KRAS activation rewires cancer cell metabolism, altering mitochondrial morphology and function. Specifically, activation of the downstream RAF-MEK-ERK effector signaling pathway leads to phosphorylation of mitochondrial fission protein DRP1, which drives mitochondrial fragmentation to support PDAC growth. In contrast, pharmacological inhibition of ERK signaling, using selective ERK1/2 inhibitor (ERKi, SCH227984), causes mitochondrial fusion and inhibits PDAC cell growth. However, the mechanistic basis by which mitochondrial fission supports PDAC proliferation remains unknown. Furthermore, it is unclear whether mitochondrial fusion is required for ERKi-mediated growth suppression. We hypothesized that preventing mitochondrial fusion by silencing mitochondrial fusion proteins OPA1 and MFN1 will yield resistance to inhibition of ERK signaling. To test this, we used two unique siRNAs targeting OPA1 or MFN1, which caused a hyper-fragmented mitochondrial phenotype. Interestingly, we found that loss of mitochondrial fusion in Pa14C cells increased the GI50 concentration of ERKi by ~40% compared to control-treated cells. This suggests that PDAC cells with hyper-fragmented mitochondria may be slightly resistant to ERKi. However, the other PDAC cell line tested (HPAC) displayed, on average, no significant changes in the GI50 concentration of ERKi. Future studies are focused on further characterizing the impact of altered mitochondrial dynamics on PDAC cell sensitivity to inhibition of KRAS downstream effectors.