CDK4/6 or MAPK blockade enhances efficacy of EGFR inhibition in oesophageal squamous cell carcinoma

• Published in: Nature communications Vol. 8; no. 1; p. 13897
• Main Authors: Zhou, Jin, Wu, Zhong, Wong, Gabrielle, Pectasides, Eirini, Nagaraja, Ankur, Stachler, Matthew, Zhang, Haikuo, Chen, Ting, Zhang, Haisheng, Liu, Jie Bin, Xu, Xinsen, Sicinska, Ewa, Sanchez-Vega, Francisco, Rustgi, Anil K., Diehl, J. Alan, Wong, Kwok-Kin, Bass, Adam J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.01.2017; Nature Publishing Group; Nature Portfolio
• Subjects: 13/95; 631/67/1504; 64/60; 692/4028/67/1059; 82/29; 82/51; 96/1; 96/31; Animals; Biomarkers; Cancer therapies; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - pathology; Cell cycle; Cell Line, Tumor; Chemotherapy; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - metabolism; Cyclin-dependent kinases; Drug Resistance, Neoplasm - drug effects; Enzyme Activation - drug effects; Epidermal growth factor; Epithelial-Mesenchymal Transition - drug effects; ErbB Receptors - antagonists & inhibitors; ErbB Receptors - genetics; Erlotinib Hydrochloride - pharmacology; Erlotinib Hydrochloride - therapeutic use; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma; Gene Amplification; Genomes; Humanities and Social Sciences; Humans; Kinases; Lung cancer; Medicine; Mice; Mitogen-Activated Protein Kinases - antagonists & inhibitors; Mitogen-Activated Protein Kinases - metabolism; multidisciplinary; Mutation; Phenotype; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proteins; Science; Science (multidisciplinary); Treatment Outcome; Tumors; Xenograft Model Antitumor Assays; New York; United States > US; Massachusetts
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13897

Oesophageal squamous cell carcinoma is a deadly disease where systemic therapy has relied upon empiric chemotherapy despite the presence of genomic alterations pointing to candidate therapeutic targets, including recurrent amplification of the gene encoding receptor tyrosine kinase epidermal growth factor receptor (EGFR). Here, we demonstrate that EGFR-targeting small-molecule inhibitors have efficacy in EGFR-amplified oesophageal squamous cell carcinoma (ESCC), but may become quickly ineffective. Resistance can occur following the emergence of epithelial–mesenchymal transition and by reactivation of the mitogen-activated protein kinase (MAPK) pathway following EGFR blockade. We demonstrate that blockade of this rebound activation with MEK (mitogen-activated protein kinase kinase) inhibition enhances EGFR inhibitor-induced apoptosis and cell cycle arrest, and delays resistance to EGFR monotherapy. Furthermore, genomic profiling shows that cell cycle regulators are altered in the majority of EGFR -amplified tumours and a combination of cyclin-dependent kinase 4/6 (CDK4/6) and EGFR inhibitors prevents the emergence of resistance in vitro and in vivo . These data suggest that upfront combination strategies targeting EGFR amplification, guided by adaptive pathway reactivation or by co-occurring genomic alterations, should be tested clinically. Oesophageal squamous cell carcinoma often develop resistance to EGFR tyrosine kinase inhibitors. Here, the authors demonstrate that inhibition of cell cycle regulators CDK4/6 or MAPK blockade enhances the efficacy of EGFR inhibitors for these tumours in mice.