Osimertinib and Selinexor Team Up Against Aggressive T-Cell Leukemia in Preclinical Study

A drug-repurposing screen of 3,067 FDA-approved compounds has yielded an unexpected pairing: osimertinib, a third-generation EGFR inhibitor best known for lung cancer, and selinexor, an exportin 1 inhibitor approved for certain blood cancers, act synergistically against T-cell acute lymphoblastic leukemia (T-ALL) cells. The study, published open access in Biomarker Research on 28 October 2026, reports that the combination depletes the oncogenic driver c-MYC, disrupts ribosome biogenesis, and triggers nucleolar stress, cooperatively pushing leukemic cells into apoptosis. In mouse xenograft models, the pairing improved survival and reduced leukemic burden with minimal toxicity to normal cells at low doses.

T-cell acute lymphoblastic leukemia is an aggressive malignancy of the blood and bone marrow with a poor prognosis, particularly in adults and in patients whose disease has relapsed or become refractory to treatment. Even with intensive multi-agent chemotherapy, outcomes remain unsatisfactory. The disease is driven by aberrant activation of oncogenic pathways, most frequently NOTCH1 and PI3K/AKT/mTOR, which converge on c-MYC to promote proliferation, survival, and metabolic reprogramming. Single-agent inhibitors targeting these pathways, such as gamma-secretase inhibitors and PI3K/AKT/mTOR inhibitors, have shown limited clinical efficacy and dose-limiting toxicities, leaving a clear need for new therapeutic strategies.

The research team, led by authors including Rushuang Xu, Shuangnian Xu, and Xi Li, began with a repurposing screen of an FDA-approved drug library comprising 3,067 compounds. That screen identified osimertinib as a potent anti-leukemia candidate, despite the fact that T-ALL cells express very low levels of EGFR, the drug’s canonical target. Analysis of the Human Protein Atlas Cell Line database showed minimal EGFR transcript abundance in MOLT-4, Jurkat, and MOLT-3 cells, and immunoblotting confirmed minimal EGFR protein in all four cell lines studied. Adding the EGFR ligand EGF did not rescue osimertinib-induced apoptosis, an early hint that the drug was acting through something other than its usual pathway.

Osimertinib induced dose-dependent cytotoxicity in four T-ALL cell lines—MOLT-4, Jurkat, CCRF/CEM, and MOLT-3—which differ in TP53 status: MOLT-3 is wild-type, Jurkat harbors a truncating R196* mutation, CCRF/CEM carries R175H and R248Q missense mutations, and MOLT-4 carries R248Q and R306* mutations. Half-maximal inhibitory concentrations at 24 hours were 6.5 µM in MOLT-4, 2.8 µM in Jurkat, 4.6 µM in CCRF/CEM, and 3.5 µM in MOLT-3, with lower values at 48 hours. The drug also induced dose-dependent apoptosis in primary T-ALL blasts obtained from four newly diagnosed patients. Cell death proved caspase-dependent: the pan-caspase inhibitor Z-VAD-FMK blocked osimertinib-induced apoptosis, while inhibitors of necroptosis and ferroptosis did not.

Mechanistic experiments showed that osimertinib promotes 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. Osimertinib did not reduce c-MYC mRNA; instead, cycloheximide chase assays showed the drug shortened the half-life of c-MYC protein, and pre-treatment with the proteasome inhibitor MG132 blocked the degradation. Cellular thermal shift and DARTS assays suggested a potential direct interaction or conformational change, although the direct molecular target remains unidentified. Z-VAD-FMK did not prevent c-MYC degradation, confirming the process is independent of caspase activation and apoptosis.

Because c-MYC drives ribosome biogenesis—the cellular machinery of protein synthesis that highly proliferative cancers depend on—the researchers hypothesized that osimertinib-mediated c-MYC suppression would create a vulnerability that selinexor could exploit. Selinexor, a selective inhibitor of exportin 1 (XPO1), blocks nuclear export of ribosomal subunits and tumor suppressor proteins. Dose-response matrix analysis using the Highest Single Agent model revealed synergistic cytotoxicity in all four T-ALL cell lines, with HSA synergy scores of 18.47 in MOLT-4, 18.68 in Jurkat, 11.20 in CCRF/CEM, and 16.03 in MOLT-3. A fixed low dose of selinexor (20 nM) markedly reduced the IC50 of osimertinib in all four lines.

At 2 µM osimertinib plus 20 nM selinexor, the combination induced greater apoptosis than either single agent in all four cell lines, accompanied by enhanced cleavage of PARP1 and caspase-3 and loss of mitochondrial membrane potential. Lower concentrations showed a more patchwork pattern: at 1 µM, the combination exceeded both single agents in three of four cell lines, and at 0.5 µM in two of four. Mechanistically, the combination caused nuclear retention of RPS6, nuclear accumulation of the ribosomal proteins RPL5 and RPL11, and nucleolar stress marked by dispersal of fibrillarin. The accumulated RPL5 and RPL11 were accompanied by decreased MDM2 protein levels, p53 stabilization and phosphorylation, BAX activation detected with the 6A7 conformational antibody, cytochrome c release into the cytoplasm, c-MYC depletion, and suppression of global protein synthesis measured by puromycin incorporation.

Selectivity testing offered a measure of reassurance. At the synergistic low-dose combination, viability of normal human bone marrow mononuclear cells remained approximately 85 percent and HEK293T cells approximately 75 percent after 48 hours, and higher concentrations showed no synergistic toxicity beyond what osimertinib alone produced. In vivo, the team used a MOLT-4 xenograft model in NSG mice. Osimertinib monotherapy at 20 mg/kg prolonged overall survival, reduced white blood cell counts, lowered the frequency of hCD45+ leukemic cells in bone marrow, and shrank the spleen. In the combination experiment, mice receiving osimertinib 10 mg/kg plus selinexor 5 mg/kg showed the greatest survival benefit, significantly outperforming both monotherapies, along with the lowest leukemic burden, reduced splenomegaly, increased cleaved caspase-3, and decreased Ki-67 in spleen and liver tissue.

The authors are candid about the study’s boundaries. The direct molecular target of osimertinib in T-ALL cells remains unknown, as does the upstream E3 ubiquitin ligase responsible for c-MYC degradation. Primary blast experiments were limited to four patients, and in vivo efficacy derives exclusively from the MOLT-4 xenograft model in immunodeficient NSG mice, without patient-derived xenografts or pharmacokinetic monitoring. Notably, the most pronounced synergy required 2 µM osimertinib, which exceeds the drug’s clinical peak plasma concentration of roughly 1 µM, and the high concentrations used in CETSA and DARTS assays exceed clinically relevant exposures. The authors frame 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, all requiring prospective validation. Both drugs are FDA-approved for other cancers, and the combination is presented as a preclinical strategy warranting further studies with pharmacokinetic monitoring, PDX models, and biomarker validation before any clinical translation.

Subject of Research: Preclinical evaluation of osimertinib combined with selinexor for T-cell acute lymphoblastic leukemia

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

Article References: Xu, R., Huang, X., Liu, J., Shang, Y., Zhang, N., Xu, J., Cheng, S., Xu, S., & Li, X. (2026). Synergistic efficacy of the EGFR inhibitor osimertinib with the XPO1 inhibitor selinexor in T-cell acute lymphoblastic leukemia. Biomarker Research, 14(1), Article 152. https://doi.org/10.1186/s40364-026-01031-w

Image Credits: AI Generated

DOI: 10.1186/s40364-026-01031-w

Keywords: T-cell acute lymphoblastic leukemia, osimertinib, selinexor, c-MYC, nucleolar stress, ribosome biogenesis, drug repurposing, XPO1 inhibitor, EGFR inhibitor, xenograft model, TP53 status, apoptosis