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Abstract
[...]HER-2 amplification has been identified as a mechanism of osimertinib acquired resistance in a patient treated with osimertinib [9], providing evidence for targeting HER-2 in this clinical setting. [...]when the cells were treated for 72 h with osimertinib before T-DM1 treatment, a cell cycle profile comparable to that of cycling control cells was observed. [...]in the cells pre-treated with osimertinib and then treated with T-DM1 for 48 h cell death was significantly reduced in respect to cells treated for 48 h with T-DM1 alone (Fig. 3d) and an up-regulation of the anti-apoptotic protein Mcl-1 and a down-regulation of the pro-apoptotic protein Bim were observed in osimertinib-pretreated cells exposed for 48 h to TDM-1 compared to cells only treated for 48 h with T-DM1 (Fig. 3e). Osimertinib is an effective treatment in NSCLC patients with T790M EGFR mutation, progressed after first-line therapy with first- or second-generation EGFR-TKIs [4]. [...]osimertinib was also evaluated in the first-line setting in patients with EGFR activating mutations compared with gefitinib or erlotinib (FLAURA Trial NCT02296125). Here we demonstrated that, differently from trastuzumab, T-DM1 showed anti-proliferative effects in PC9, PC9-T790M and H1975 cells and exerted an additive effect when combined with osimertinib in terms of inhibition of proliferation, cell death and ADCC induction. Because osimertinib is highly effective in mutated NSCLC cell lines, the addition of T-DM1 caused a modest benefit when evaluated in short-term growth assay, by contrast the combination significantly delayed the acquired resistance to osimertinib in PC9-T790M and in the less osimertinib-sensitive model H1975.