Abstract
AZD9291 (osimertinib) is approved for standard care in patients with EGFR T790M-positive non-small cell lung cancer (NSCLC) after prior EGFR TKI progression. Furthermore, AZD9291 is now being evaluated as a first-line treatment for NSCLC patients with activation EGFR mutations. Based on previous experiments, resistance to AZD9291 as a first-line treatment may also emerge. Thus, identification and understanding of resistance mechanisms to AZD9291 as a first-line treatment can help direct development of future therapies. AZD9291-resistant cells (PC9/AZDR) were established using EGFR inhibitor-naïve PC9 cells. Resistance mechanisms were analyzed using next-generation sequencing (NGS) and a proteome profiler array. Resistance to AZD9291 developed through aberrant activation of ERK signaling by an EGFR-independent mechanism. The combination of a MEK inhibitor with AZD9291 restored the sensitivity of PC9/AZDR cells in vitro and in vivo. PC9/AZDR cells also showed increased MET expression and an HRAS G13R mutation. In addition, maspin expression was higher after AZD9291 treatment in PC9/AZDR cells. Sustained ERK activation confers resistance to AZD9291 as a first-line therapy. Thus, co-targeting EGFR and MEK may be an effective strategy to overcome resistance to AZD9291.
Highlights
Targeted therapy using the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib/ erlotinib and second-generation afatinib is substantially better than standard chemotherapy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations [1]
PC9/AZDR cells were resistant to other EGFR TKIs such as CO1686, afatinib, gefitinib, and erlotinib (Fig 1C)
As the EGFR C797S mutation was the most common resistance mechanism to AZD9291 in T790M-positive NSCLC patients who failed prior EGFR TKIs [8, 13], we analyzed this mutation in PC9/AZDR cells
Summary
Targeted therapy using the first-generation EGFR tyrosine kinase inhibitors (TKIs) gefitinib/ erlotinib and second-generation afatinib is substantially better than standard chemotherapy in patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations [1]. Almost all patients exhibit acquired resistance to EGFR TKIs and will experience relapse within one year. Acquired resistance to AZD9291 as an upfront treatment. NRF-2017M3C9A6044632) and by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No 2017M3A9G5060252) (JMS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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