TY - JOUR
T1 - Targeting of MEK and Autophagy in Pancreatic Adenocarcinoma and Analysis of Treatment Sensitivity in Preclinical and Clinical Models
T2 - MEKiAUTO
AU - Labadie, Brian W.
AU - Obradovic, Aleksandar
AU - Raufi, Alexander G.
AU - Wasko, Urszula N.
AU - Tomassoni, Lorenzo
AU - Ge, Liner
AU - May, Michael
AU - Vij, Manan
AU - Li, Li
AU - Ross, Isabelle
AU - Sedycius, Sarah S.
AU - Sender, Naomi
AU - Dreher, Nickolas
AU - Wu, Linda
AU - Abuzaid, Sinan
AU - Iuga, Alina
AU - Shah, Parin
AU - Wulfkuhle, Julia D.
AU - Bates, Susan
AU - Wong, Winston
AU - Pellicciotta, Ilenia
AU - Lyashchenko, Alex K.
AU - Safran, Howard
AU - Izar, Benjamin
AU - Petricoin, Emanuel F.
AU - Cremers, Serge
AU - Tan, Aik Choon
AU - Lee, Shing
AU - Califano, Andrea
AU - Olive, Kenneth P.
AU - Manji, Gulam A.
N1 - Publisher Copyright:
© 2026 by American Society of Clinical Oncology
PY - 2026/6
Y1 - 2026/6
N2 - PURPOSE – Combined mitogen-activated protein kinase kinase (MEK) and autophagy inhibition has shown antitumor efficacy in preclinical pancreatic ductal adenocarcinoma (PDAC) models. We evaluated this therapeutic strategy in the autochthonous K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mouse model and in the MEKiAUTO phase I trial of patients with metastatic KRAS-mutant PDAC, with or without anti–PD-L1 antibody atezolizumab.METHODS – Short-term intervention studies in KPC mice and a phase I clinical trial based on a time-to-event continual reassessment method design were performed. Tumor response was assessed through multiplex immunofluorescence, reverse-phase protein array, and single-nucleus RNA sequencing of serial tumor specimens.RESULTS – MEK and autophagy inhibition suppressed tumor growth in KPC mice. In the clinical trial, 14 patients were treated and four experienced a dose-limiting toxicity. The median progression-free survival (PFS) and overall survival were 7.7 weeks (95% CI, 6 to 15.6) and 20.7 weeks (95% CI, 15.6 to 46.1), respectively. snRNA-seq on paired tumor biopsies identified substantial malignant cell heterogeneity, including an epithelial subtype enriched for autophagy and mitogen-activated protein kinase (MAPK) signaling that decreased after treatment. Higher baseline abundance of this subtype correlated with longer PFS but was rare in TCGA PDAC tumors. By contrast, KPC tumors and PDAC cell lines exhibited reduced heterogeneity and uniform enrichment of this MAPK/autophagy-high state, consistent with their stronger preclinical responses.CONCLUSION – Combined MEK and autophagy inhibition showed limited tolerability in human PDAC. Divergent efficacy between preclinical and clinical settings likely reflects differences in tumor cell state heterogeneity between models. Integration of diverse, representative preclinical models is critical to guide development of effective therapies in PDAC.
AB - PURPOSE – Combined mitogen-activated protein kinase kinase (MEK) and autophagy inhibition has shown antitumor efficacy in preclinical pancreatic ductal adenocarcinoma (PDAC) models. We evaluated this therapeutic strategy in the autochthonous K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mouse model and in the MEKiAUTO phase I trial of patients with metastatic KRAS-mutant PDAC, with or without anti–PD-L1 antibody atezolizumab.METHODS – Short-term intervention studies in KPC mice and a phase I clinical trial based on a time-to-event continual reassessment method design were performed. Tumor response was assessed through multiplex immunofluorescence, reverse-phase protein array, and single-nucleus RNA sequencing of serial tumor specimens.RESULTS – MEK and autophagy inhibition suppressed tumor growth in KPC mice. In the clinical trial, 14 patients were treated and four experienced a dose-limiting toxicity. The median progression-free survival (PFS) and overall survival were 7.7 weeks (95% CI, 6 to 15.6) and 20.7 weeks (95% CI, 15.6 to 46.1), respectively. snRNA-seq on paired tumor biopsies identified substantial malignant cell heterogeneity, including an epithelial subtype enriched for autophagy and mitogen-activated protein kinase (MAPK) signaling that decreased after treatment. Higher baseline abundance of this subtype correlated with longer PFS but was rare in TCGA PDAC tumors. By contrast, KPC tumors and PDAC cell lines exhibited reduced heterogeneity and uniform enrichment of this MAPK/autophagy-high state, consistent with their stronger preclinical responses.CONCLUSION – Combined MEK and autophagy inhibition showed limited tolerability in human PDAC. Divergent efficacy between preclinical and clinical settings likely reflects differences in tumor cell state heterogeneity between models. Integration of diverse, representative preclinical models is critical to guide development of effective therapies in PDAC.
UR - https://www.scopus.com/pages/publications/105043509303
U2 - 10.1200/PO-26-00138
DO - 10.1200/PO-26-00138
M3 - Article
C2 - 42284543
AN - SCOPUS:105043509303
SN - 2473-4284
VL - 10
JO - JCO Precision Oncology
JF - JCO Precision Oncology
IS - 6
M1 - e2600138
ER -