Osimertinib synergizes selinexor on anti-tumor effect by targeting c-MYC in T-cell acute lymphoblastic leukemia Free

Background

Adult T-cell acute lymphoblastic leukemia (T-ALL), a hematological malignancy derived from T lymphocyte hematopoietic stem cells, is highly aggressive and has a poor prognosis, with a 5-year survival rate of less than 40% under current treatment. In T-ALL, aberrant expression of c-MYC interferes with T-cell differentiation program. Nuclear EGFR is known to function as a co-transcription factor of Stat3 to enhance the transcription of the c-MYC. Besides, exportin-1 (XPO1) is a critical mediator of nuclear export, which is essential for regulating the cell cycle and proliferation of normal and malignant tissues. Increased expression of XPO1 has been observed in various types of cancer, including ALL. In this study, we investigated the combined effects of Osimertinib and Selinexor in T-ALL and explored the underlying mechanisms.

Methods

Candidate therapeutic drugs were selected through drug screening, and synergyfinder+ analysis was performed for a synergistic effect. CCK-8, flow cytometry and colony formation assays were used for the effects of single or combination therapy on the proliferation, apoptosis.Furthermore, a tumor xenograft model was established to estimate the in vivo efficacy of the drug combination. The molecular mechanism of drug combination against T-ALL was explored through multi-omics analysis, western blot and qPCR.

Results

Osimertinib, a tyrosine kinase inhibitor targeting EGFR, was selected from the FDA-approved drug library. Treatment of Osimertinib or Selinexor significantly led to cell proliferation arrest of MOLT-4 and Jurkat cells in a dose-dependent manner. The combination of Osimertinib with Selinexor significantly enhanced the cell proliferation arrest of MOLT-4 and Jurkat cells versus the single drug controls, and synergyfinder+ analysis exhibited a synergistic effect of the drug combination in the cells. Compared with monotherapy, the apoptosis rate of T-ALL induced by combined therapy was significantly increased, mitochondrial membrane potential decreased, expression of apoptosis-related proteins decreased, and the number of colony formation reduced. In vivo, drug combination showed a favorable anti-tumor effect compared to a single treatment. To gain insight into the underlying mechanism of the synergy, we observed the effect of the drugs on the expression of c-MYC. Results showed that the combination of Osimertinib with Selinexor significantly down-regulated the expression of c-MYC compared to the single-drug controls in MOLT-4 and Jurkat cells. Taken together, our data indicated the synergistic effect of Osimertinib with Selinexor on cell proliferation arrest and apoptosis by down-regulation of c-MYC expression. Based on these findings, we believe that the combination of Osimertinib and Selinexor provides a promising strategy for overcoming the treatment of T-ALL.

Conclusions

The combination of Osimertinib with Selinexor has synergistic effects on cell proliferation arrest and apoptosis in T-ALL by targeting c-MYC both in vitro and in vivo, providing a promising strategy for overcoming the treatment of T-ALL. Further clinical evaluation is required.