Synergistic efficacy of the EGFR inhibitor osimertinib with the XPO1 inhibitor selinexor in T-cell acute lymphoblastic leukemia

Abstract Background T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy with poor prognosis, especially in relapsed/refractory patients. Aberrant PI3K/AKT/mTOR and NOTCH1 signaling converge on c-MYC to drive proliferation and ribosome biogenesis, but single-agent inhibitors targeting these pathways have shown limited clinical efficacy. Methods An FDA-approved drug library screen identified osimertinib as a candidate anti-T-ALL agent. Its efficacy and mechanism were evaluated in four T-ALL cell lines (MOLT-4, Jurkat, CCRF/CEM, and MOLT-3) with different TP53 statuses and in primary T-ALL blasts. Combination studies with selinexor, an exportin 1 (XPO1) inhibitor, were performed. Multi-omics, biochemical, and functional assays were used, and efficacy and toxicity were assessed in T-ALL xenograft models. Results Osimertinib suppressed leukemic progression in vivo by promoting proteasome-dependent degradation of c-MYC through a non-canonical, EGFR-independent pathway that cannot be fully explained by inhibition of PI3K/AKT/mTOR or NOTCH1 signaling alone. This c-MYC suppression impaired ribosome biogenesis, and combining osimertinib with selinexor further disrupted this process. The combination increased apoptosis at low concentrations (0.5-2 µM osimertinib plus 20 nM selinexor), with clear synergy at 2 µM in all four T-ALL cell lines. Mechanistically, the combination caused nuclear retention of RPS6, nuclear accumulation of RPL5/RPL11, nucleolar stress (fibrillarin dispersal), decreased MDM2 protein levels, p53 stabilization, BAX activation (6A7), cytochrome c release, c-MYC depletion, and translational suppression. In vivo, the combination improved survival and reduced leukemic burden with minimal toxicity to normal cells at low doses. Potential biomarkers include c-MYC dependency and TP53 status as candidate stratification factors, and treatment-induced c-MYC depletion and RPL5/RPL11 nuclear accumulation as candidate pharmacodynamic biomarkers. Conclusions Osimertinib plus selinexor depletes c-MYC, induces nucleolar stress, and suppresses translation, which together drive T-ALL cell apoptosis. This mechanism-driven combination shows preclinical efficacy with limited toxicity in the normal-cell and xenograft models tested. Further studies incorporating pharmacokinetic monitoring, PDX models, and prospective validation of candidate biomarkers such as c-MYC dependency, TP53 status, and RPL5/RPL11 nuclear accumulation are warranted before clinical translation.