Abstract
Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076. Phospho-histone H3 (pH3), a major product of AURKB, is increased in most resistant cells and treatment with AURKB inhibitors reduces the levels of pH3, triggering G1/S arrest and polyploidy. Senescence is subsequently induced in cells with acquired mutations while, in their absence, polyploidy is followed by cell death. Finally, in NSCLC patients, pH3 levels are increased after progression on EGFR TKIs and high pH3 baseline correlates with shorter survival. Our results reveal that AURKB activation is associated with acquired resistance to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing to anti-EGFR therapy and not carrying resistance mutations.
Highlights
Non-small cell lung cancer (NSCLC) tumors harboring mutations in Epidermal Growth Factor Receptor (EGFR) relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs)
In this study, we used three panels of cell lines with acquired resistance EGFR TKIs; two were derived from PC9 cells, which carry a deletion in exon 19 of EGFR; and one from 11–18 cells, which harbor a p.L858R mutation
The eighteen cell lines of our panels presented a variety of molecular alterations, including acquisition or loss of the p.T790M, emergence of NRAS mutations, MET activation and AXL, EGFR, and FGFR1 upregulation
Summary
Resistance to EGFR TKIs in PC9 cells is associated with different alterations. We had previously generated six EGFR-TKIresistant cell lines by treating EGFR-mut, TKI-sensitive PC9 cells with increasing concentrations of gefitinib (PC9-GR1–5) or erlotinib (PC9-ER). The AURKA/AURKB inhibitor tozasertib was very active against non-p.T790M cells, the differences in the IC50s were less pronounced than in the case of barasertib In view of these results, we included in our study the H1975 NSCLC cell line, a model of intrinsic resistance to EGFR TKIs that harbors a p.L858R and a p.T790M mutation in EGFR at 75% allelic fraction (Table 1). No significant differences were observed in the case of gefitinib, BGB324 or other TKIs. In contrast, the partly silenced clones showed a >100-fold increase in the IC50s for barasertib and S49076, compared to parental or control-transfected PC9-ER cells (Fig. 3e and Supplementary Table 1), confirming that AURKB is the main target of both drugs in PC9-ER. When the same analysis was performed for Ki67, mitotic pH3 or non-mitotic pH3 separately, the differences in OS between the groups did not reach statistical significance (Supplementary Table 3)
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