A Novel Molecular Target in EGFR-Mutant Non-Small Cell Lung Cancer Treated With a Combination of Osimertinib and Pemetrexed

Overcoming acquired resistance to the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib is currently an important clinical issue in treating EGFR-mutant non-small cell lung cancer (NSCLC) patients. EGFR-TKI may synergize with chemotherapy and offer novel treatment strategies for overcoming acquired resistance. Here, we evaluate the therapeutic potential of combining osimertinib with pemetrexed and clarify the underlying molecular mechanisms. Gene expression microarrays were used to assess gene expression on exposure to osimertinib in the presence or absence of pemetrexed and we established cell lines resistant to osimertinib as well as those resistant to osimertinib+pemetrexed in order to explore mechanisms of resistance. Osimertinib+pemetrexed treatment significantly delayed the emergence of resistance relative to monotherapy in vitro and in vivo . Microarray analysis revealed significantly downregulated expression of the anti-apoptotic gene PLK1 in cells treated with osimertinib+pemetrexed. Consistent with this, cell lines resistant to osimertinib or to osimertinib+pemetrexed, exhibited overexpression of PLK1. Accordingly, PLK1 inhibition by siRNA or PLK1 inhibitor volasertib inhibited proliferation by inducing apoptosis in these resistant cell lines. Blocking PLK1 contributes to mediating the synergistic antiproliferative effect of osimertinib+pemetrexed in EGFR-mutant NSCLC cells. PLK1 overexpression may be a critical mechanism responsible for the acquired resistance of such mutants to osimertinib+pemetrexed.