Targeting mitochondrial function as a therapeutic approach for pancreatic ductal adenocarcinoma

The KRAS oncogene is mutationally activated in over 95% of pancreatic ductal adenocarcinoma (PDAC) patients. Aberrant KRAS function drives PDAC growth in part through rewiring cancer cell metabolism and inducing alterations to mitochondrial function. Recent evidence suggests that PDAC cells rely on mitochondrial activity for their survival and that targeting mitochondrial function is a promising therapeutic strategy. KRAS-mutant PDAC cells are characterized by fragmented mitochondria to support their growth, which is mediated through activation of the key KRAS effector, the RAF-MEK- ERK MAPK protein kinase cascade. We have determined that treatment of KRASG12D- mutant PDAC cells with the KRASG12D-selective inhibitor MRTX1133 (KRASi) or ERK1/2- selective inhibitor SCH772984 (ERKi) promoted mitochondrial fusion and suppressed PDAC cell growth. However, whether KRASi- or ERKi-induced growth suppression depends on mitochondrial fusion remains unresolved. We used a genetic siRNA- mediated approach to suppress the expression of mitochondrial fusion proteins OPA1 or MFN1, which caused a hyper-fragmented mitochondrial phenotype. Although these cells were resistant to KRASi-/ERKi-induced mitochondrial fusion, they remained sensitive to KRASi/ERKi-induced growth suppression. Thus, mitochondrial fission alone is not sufficient to support PDAC growth. Nevertheless, promising anticancer compounds that target mitochondrial function beyond changes to mitochondrial dynamics are not well characterized in PDAC. Of these, we evaluated ONC201, a clinical candidate agonist of the mitochondrial matrix protease ClpP, as a potential therapeutic target for PDAC. We found that ONC201 hyperactivated ClpP, causing proteolytic degradation of a spectrum of mitochondrial proteins such as those involved in oxidative phosphorylation (OXPHOS). Furthermore, ONC201-induced activation of ClpP inhibited PDAC cell growth and impaired mitochondrial ATP production. ONC201 treatment also resulted in a compensatory increase in glycolysis to offset the loss of OXPHOS. Concurrent treatment with ONC201 and ERKi, which suppresses glycolysis, further sensitized cells to ERK inhibition. Ongoing studies are addressing whether ONC201-induced mitochondrial dysfunction will also sensitize PDAC cells to direct KRASG12D inhibitors. Together, these studies will evaluate the potential of combining mitochondrial function inhibitors with direct KRAS-ERK pathway inhibitors for PDAC treatment.