Osimertinib induced human immortalized keratinocyte apoptosis by activating the MAPK signaling pathway

This study investigated its toxic effects on human immortalized keratinocytes (HaCaT). The effect of osimertinib on the proliferation and apoptosis of HaCaT cells was tested by cell counting kit (CCK)-8 assay, proliferation (EdU, colony formation), and apoptosis (flow cytometry). Osimertinib (750 nM) significantly inhibited the proliferation of HaCaT cells and promoted its apoptosis. Transcriptome analysis and qRT-PCR revealed that EREG and AREG were downregulated after the treatment of osimertinib. KEGG analysis suggested that osimertinib exposure caused the abnormality in MAPK signaling pathway and Western blotting suggested that the MAPK signaling pathway was upregulated after the treatment of osimertinib. Finally, rescue experiments further confirmed that the overexpression of EREG and AREG significantly rescued HaCaT cells apoptosis and the abnormality in MAPK signaling pathway Osimertinib could activate the MAPK signaling pathway by downregulating EREG and AREG in HaCaT cells. Our finding highlights the impact on the toxicities of osimertinib in HaCaT cells and will provide the therapeutic target for osimertinib-induced skin toxicities.