Role of endoscopic ultrasound in the molecular diagnosis of pancreatic cancer

Pancreatic ductal adenocarcinoma remains one of the most deadly types of tumor. Endoscopic ultrasoundguided fine-needle aspiration(EUS-FNA) is a safe, cost-effective, and accurate technique for evaluating and staging pancreatic tumors. However, EUS-FNA may be inconclusive or doubtful in up to 20% of cases. This review underlines the clinical interest of the molecular analysis of samples obtained by EUS-FNA in assessing diagnosis or prognosis of pancreatic cancer, especially in locally advanced tumors. On EUS-FNA materials DNA, mRNA and miRNA can be extracted, amplified, quantified and subjected to methylation assay. Kras mutation assay, improves diagnosis of pancreatic cancer. When facing to clinical and radiological presentations of pseudo-tumorous chronic pancreatitis, wildtype Kras is evocative of benignity. Conversely, in front of a pancreatic mass suspected of malignancy, a mutated Kras is highly evocative of pancreatic adenocarci-noma. This strategy can reduce false-negative diagnoses, avoids the delay of making decisions and reduces loss of surgical resectability. Similar approaches are conducted using analysis of miRNA expression as well as Mucin or markers of invasion(S100P, S100A6, PLAT or PLAU). Beyond the diagnosis approach, the prediction of response to treatment can be also investigated form biomarkers expression within EUS-FNA materials.

Targeting metabolic vulnerability in mitochondria conquers MEK inhibitor resistance in KRAS-mutant lung cancer

MEK is a canonical effector of mutant KRAS;however,MEK inhibitors fail to yield satisfactory clinical outcomes in KRAS-mutant cancers.Here,we identified mitochondrial oxidative phosphorylation(OXPHOS)induction as a profound metabolic alteration to confer KRAS-mutant non-small cell lung cancer(NSCLC)resistance to the clinical MEK inhibitor trametinib.Metabolic flux analysis demonstrated that pyruvate metabolism and fatty acid oxidation were markedly enhanced and coordinately powered the OXPHOS system in resistant cells after trametinib treatment,satisfying their energy demand and protecting them from apoptosis.As molecular events in this process,the pyruvate dehydrogenase complex(PDHc)and carnitine palmitoyl transferase IA(CPTIA),two rate-limiting enzymes that control the metabolic flux of pyruvate and palmitic acid to mitochondrial respiration were activated through phosphorylation and transcriptional regulation.Importantly,the co-administration of trametinib and IACS-010759,a clinical mitochondrial complex I inhibitor that blocks OXPHOS,significantly impeded tumor growth and prolonged mouse survival.Overall,our findings reveal that MEK inhibitor therapy creates a metabolic vulnerability in the mitochondria and further develop an effective combinatorial strategy to circumvent MEK inhibitors resistance in KRAS-driven NSCLC.