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.
Highlights
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)
We evaluated our panel of EGFR-amplified oesophageal squamous cell carcinoma (ESCC) models for their in vitro sensitivity to erlotinib, a reversible small-molecule EGFR inhibitor, and afatinib, an irreversible small-molecule EGFR/ERBB2 inhibitor, finding a range of sensitivities (Fig. 1c and Supplementary Table 1)
The initial effects of combined EGFR and cyclin-dependent kinase 4/6 (CDK4/6) inhibition in short-term viability assays were of only modest effects, we evaluated the effect of palbociclib upon the emergence of resistance to EGFR-directed monotherapy, and found that erlotinib þ palbociclib showed the ability of blocking the onset of resistance in vitro
Summary
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). 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. When targeted agents are introduced into the clinic, the patients who initially respond typically subsequently develop acquired resistance[13,14,15,16,17] When such resistance is induced by a clear secondary mutation, such as a secondary EGFR T790M mutation in non-small-cell lung cancer, targeted use of an appropriate secondary inhibitor can be highly effective. By addressing fundamental questions regarding the initial drug sensitivity of these models, the emergence of resistance and mechanisms of blocking resistance, we hope to speed our ability to bring optimal therapeutic strategies forward into clinical testing for these cancers
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