Peer-Reviewed Publication
Cancer Lett2026;654218607.August 28, 2026Journal Article
EGFR S442 ectodomain mutation confers cetuximab resistance that can be overcome by ERBB2 blockade with trastuzumab-deruxtecan.
Sarah J Harmych1, Neeraj Joshi2, Hidenori Tanaka3, Galina Bogatcheva2, Marisol A Ramirez4, Ramona Graves-Deal2, Claiborne W Tydings5, Marina T Elia2, Hunter R Lischwe Mueller6, Isabella M Silvestri6, Khaw Ti Ning6, Claudia C Wahoski7, Chelsie K Sievers2, James N Higginbotham2, Maria Johnson Irudayam2, Frank L Revetta8, Zhiguo Zhao4, Jeffrey L Franklin2, Binyam Yilma9, Tina M O'Grady9, Stamatina Fragkogianni9, Metamia Ciampricotti9, M Kay Washington8, Xingyi Guo10, Christine M Lovly11, Allison S Walker12, Jens Meiler13, Krishna C Mudumbi14, Qi Liu4, Robert J Coffey15, Eben Rosenthal3, Bhuminder Singh16
1Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.
2Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
3Department of Otolaryngology - Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
4Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
5Department of Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN, USA.
6Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA.
7Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Program in Cancer Biology, Vanderbilt University, Nashville, TN, 37232, USA.
8Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
9Tempus AI Inc., Chicago, IL, 60654, USA.
10Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
11Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, 91010, USA.
12Department of Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN, USA; Department of Biological Sciences, Vanderbilt University, Nashville, TN, 37232, USA.
13Department of Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN, USA; Department of Pharmacology, Center for Structural Biology, Institute of Chemical Biology, Center for Applied Artificial Intelligence in Protein Dynamics, Vanderbilt University, Nashville, TN, 37232, USA; Institute for Drug Discovery, Faculty of Medicine, Faculty of Mathematics and Informatics, Faculty of Chemistry and Mineralogy, Leipzig University Medical School, Leipzig, SAC, 04103, Germany; Center for Scalable Data Analytics and Artificial Intelligence ScaDS.AI and School of Embedded Composite Artificial Intelligence SECAI, Dresden/Leipzig, Germany.
14Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
15Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
16Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA. Electronic address: bhuminder.singh@vumc.org.
Abstract
Epidermal growth factor receptor (EGFR) is an oncogenic driver in multiple cancers and a therapeutic target of tyrosine kinase inhibitors and neutralizing monoclonal antibodies. However, resistance to EGFR-targeted therapies, particularly the anti-EGFR antibody cetuximab, remains a clinical challenge in colorectal (CRC) and head and neck (HNSCC) cancers. Cetuximab exerts its antitumor activity by…
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