Synergistic efficacy of the EGFR inhibitor osimertinib with the XPO1 inhibitor selinexor in T-cell acute lymphoblastic leukemia.
6 affiliations
- 1Department of Hematology, Daping Hospital (Army Medical Center of PLA), Army Medical University (Third Military Medical University), Chongqing, China.
- 2Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China.
- 3Center for Hematology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
- 4Center for Hematology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China. [email protected].
- 5Department of Hematology, Daping Hospital (Army Medical Center of PLA), Army Medical University (Third Military Medical University), Chongqing, China. [email protected].
- 6Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, China. [email protected].
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.
Related
- Selinexor enhances temozolomide efficacy in glioblastoma through modulation of multiple resistance-associated mechanisms
- Efficacy analysis and adverse event management of selinexor in the treatment of relapsed/refractory multiple myeloma.
- Efficacy and safety of osimertinib combined with anlotinib in EGFR-mutant non-squamous non-small cell lung cancer with gradual progression after first-line osimertinib therapy: a single-center retrospective cohort study
- mTORC1 inhibition upregulates CD20 and enhances anti-CD20 antibody efficacy in B-cell precursor acute lymphoblastic leukemia
- Nanomolar anti-SARS-CoV-2 Omicron activity of the host-directed TMPRSS2 inhibitor N-0385 and synergistic action with direct-acting antivirals
BibTeX
@article{xu2026synergistic,
title = {{Synergistic efficacy of the EGFR inhibitor osimertinib with the XPO1 inhibitor selinexor in T-cell acute lymphoblastic leukemia.}},
author = {Rushuang Xu and Xiangtao Huang and Jia Liu and Yingying Shang and Na Zhang and Jiegang Xu and Shidi Cheng and Shuangnian Xu and Xi Li},
journal = {Biomarker research},
year = {2026},
month = oct,
doi = {10.1186/s40364-026-01031-w},
url = {https://europepmc.org/article/MED/42958372},
note = {CC BY},
}
RIS
TY - JOUR
TI - Synergistic efficacy of the EGFR inhibitor osimertinib with the XPO1 inhibitor selinexor in T-cell acute lymphoblastic leukemia.
AU - Rushuang Xu
AU - Xiangtao Huang
AU - Jia Liu
AU - Yingying Shang
AU - Na Zhang
AU - Jiegang Xu
AU - Shidi Cheng
AU - Shuangnian Xu
AU - Xi Li
PY - 2026
DA - 2026/10/28
JO - Biomarker research
DO - 10.1186/s40364-026-01031-w
UR - https://europepmc.org/article/MED/42958372
AB - 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.
SN - 2050-7771
ER -