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

Jin Zhou, Zhong Wu, Gabrielle Wong, Eirini Pectasides, Ankur Nagaraja, Matthew Stachler, Haikuo Zhang, Ting Chen, Haisheng Zhang, Jie Bin Liu, Xinsen Xu, Ewa Sicinska, Francisco Sanchez-Vega, Anil K. Rustgi, J. Alan Diehl, Kwok-Kin Wong and Adam J. Bass ()
Additional contact information
Jin Zhou: Dana-Farber Cancer Institute
Zhong Wu: Dana-Farber Cancer Institute
Gabrielle Wong: Dana-Farber Cancer Institute
Eirini Pectasides: Dana-Farber Cancer Institute
Ankur Nagaraja: Dana-Farber Cancer Institute
Matthew Stachler: Dana-Farber Cancer Institute
Haikuo Zhang: Dana-Farber Cancer Institute
Ting Chen: Dana-Farber Cancer Institute
Haisheng Zhang: Dana-Farber Cancer Institute
Jie Bin Liu: Dana-Farber Cancer Institute
Xinsen Xu: Dana-Farber Cancer Institute
Ewa Sicinska: Dana-Farber Cancer Institute
Francisco Sanchez-Vega: Memorial Sloan-Kettering Cancer Center
Anil K. Rustgi: University of Pennsylvania School of Medicine
J. Alan Diehl: Hollings Cancer Center, The Medical University of South Carolina
Kwok-Kin Wong: Dana-Farber Cancer Institute
Adam J. Bass: Dana-Farber Cancer Institute

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: 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.

Date: 2017
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/ncomms13897 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_ncomms13897

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/ncomms13897

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().