Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer

Ashenafi Bulle, Peng Liu, Kuljeet Seehra, Sapana Bansod, Yali Chen, Kiran Zahra, Vikas Somani, Iftikhar Ali Khawar, Hung-Po Chen, Paarth B. Dodhiawala, Lin Li, Yutong Geng, Chia-Kuei Mo, Jay Mahsl, Li Ding, Ramaswamy Govindan, Sherri Davies, Jacqueline Mudd, William G. Hawkins, Ryan C. Fields, David G. DeNardo, Deborah Knoerzer, Jason M. Held, Patrick M. Grierson, Andrea Wang-Gillam, Marianna B. Ruzinova and Kian-Huat Lim ()
Additional contact information
Ashenafi Bulle: Washington University School of Medicine
Peng Liu: Washington University School of Medicine
Kuljeet Seehra: Washington University School of Medicine
Sapana Bansod: Washington University School of Medicine
Yali Chen: Washington University School of Medicine
Kiran Zahra: Washington University School of Medicine
Vikas Somani: Washington University School of Medicine
Iftikhar Ali Khawar: Washington University School of Medicine
Hung-Po Chen: Washington University School of Medicine
Paarth B. Dodhiawala: Washington University School of Medicine
Lin Li: Washington University School of Medicine
Yutong Geng: Washington University School of Medicine
Chia-Kuei Mo: Washington University School of Medicine
Jay Mahsl: Washington University School of Medicine
Li Ding: Washington University School of Medicine
Ramaswamy Govindan: Washington University School of Medicine
Sherri Davies: Washington University School of Medicine
Jacqueline Mudd: Washington University School of Medicine
William G. Hawkins: Washington University School of Medicine
Ryan C. Fields: Washington University School of Medicine
David G. DeNardo: Washington University School of Medicine
Deborah Knoerzer: BioMed Valley Discoveries
Jason M. Held: Washington University School of Medicine
Patrick M. Grierson: Washington University School of Medicine
Andrea Wang-Gillam: Washington University School of Medicine
Marianna B. Ruzinova: Washington University School of Medicine
Kian-Huat Lim: Washington University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-46811-w

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