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Nat Commun DOI:10.1038/ncomms13897

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

Publication TypeJournal Article
Year of Publication2017
AuthorsZhou, J, Wu, Z, Wong, G, Pectasides, E, Nagaraja, A, Stachler, M, Zhang, H, Chen, T, Zhang, H, Bin Liu, J, Xu, X, Sicinska, E, Sanchez-Vega, F, Rustgi, AK, J Diehl, A, Wong, K-K, Bass, AJ
JournalNat Commun
Volume8
Pages13897
Date Published2017 Jan 06
ISSN2041-1723
Abstract

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.

DOI10.1038/ncomms13897
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/28059068?dopt=Abstract

Alternate JournalNat Commun
PubMed ID28059068
PubMed Central IDPMC5227099
Grant ListR01 CA187119 / CA / NCI NIH HHS / United States
R01 CA196932 / CA / NCI NIH HHS / United States
P30 DK050306 / DK / NIDDK NIH HHS / United States
R01 DK056645 / DK / NIDDK NIH HHS / United States
P01 CA098101 / CA / NCI NIH HHS / United States
R01 DK060694 / DK / NIDDK NIH HHS / United States