학술논문
Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer.
Document Type
Academic Journal
Author
Bulle A; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Liu P; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, China.; Seehra K; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Bansod S; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Chen Y; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Zahra K; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Somani V; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Khawar IA; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Chen HP; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Dodhiawala PB; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Li L; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Geng Y; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Mo CK; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Mahsl J; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Ding L; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Govindan R; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Davies S; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Mudd J; Section of Hepatobiliary Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Hawkins WG; Section of Hepatobiliary Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Fields RC; Section of Hepatobiliary Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, 63110, USA.; DeNardo DG; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Knoerzer D; BioMed Valley Discoveries, Kansas City, MO, 64111, USA.; Held JM; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Grierson PM; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Wang-Gillam A; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Ruzinova MB; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.; Lim KH; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO, 63110, USA. kian-huat.lim@wustl.edu.
Source
Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
Subject
Language
English
Abstract
Targeting the mitogen-activated protein kinase (MAPK) cascade in pancreatic ductal adenocarcinoma (PDAC) remains clinically unsuccessful. We aim to develop a MAPK inhibitor-based therapeutic combination with strong preclinical efficacy. Utilizing a reverse-phase protein array, we observe rapid phospho-activation of human epidermal growth factor receptor 2 (HER2) in PDAC cells upon pharmacological MAPK inhibition. Mechanistically, MAPK inhibitors lead to swift proteasomal degradation of dual-specificity phosphatase 6 (DUSP6). The carboxy terminus of HER2, containing a TEY motif also present in extracellular signal-regulated kinase 1/2 (ERK1/2), facilitates binding with DUSP6, enhancing its phosphatase activity to dephosphorylate HER2. In the presence of MAPK inhibitors, DUSP6 dissociates from the protective effect of the RING E3 ligase tripartite motif containing 21, resulting in its degradation. In PDAC patient-derived xenograft (PDX) models, combining ERK and HER inhibitors slows tumour growth and requires cytotoxic chemotherapy to achieve tumour regression. Alternatively, MAPK inhibitors with trastuzumab deruxtecan, an anti-HER2 antibody conjugated with cytotoxic chemotherapy, lead to sustained tumour regression in most tested PDXs without causing noticeable toxicity. Additionally, KRAS inhibitors also activate HER2, supporting testing the combination of KRAS inhibitors and trastuzumab deruxtecan in PDAC. This study identifies a rational and promising therapeutic combination for clinical testing in PDAC patients.
(© 2024. The Author(s).)
(© 2024. The Author(s).)