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Exploring Resistance to ETS Targeting Agents in Diffuse Large B-Cell Lymphoma.
Filippo Spriano1, Luciano Cascione1,2, Chiara Tarantelli1
1Institute of Oncology Research, Faculty of Biomedical Sciences, USI, Bellinzona, Switzerland.
Cancer Medicine
|May 14, 2026
Summary
Mechanisms of resistance to ETS inhibition in diffuse large B-cell lymphoma (DLBCL) were explored. Findings reveal diverse resistance pathways, suggesting combination therapies like venetoclax and selinexor may overcome treatment challenges.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Diffuse large B-cell lymphoma (DLBCL) presents therapeutic challenges beyond standard immunochemotherapy.
- ETS transcription factors are implicated in DLBCL pathogenesis and are targeted by TK216.
- Understanding resistance mechanisms to TK216 is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the mechanisms of resistance to the ETS inhibitor TK216 in DLBCL.
- To identify distinct patterns of resistance and potential therapeutic vulnerabilities.
Main Methods:
- Generation of TK216-resistant DLBCL cell lines (U2932).
- Transcriptomic and mutational analyses to characterize resistance mechanisms.
- Pharmacologic screening to identify sensitivities and resistance profiles.
Main Results:
- Resistant clones showed increased IC50 values and loss of G2-M arrest.
- Three resistance patterns identified: MDR1/ABCB1 overexpression, Cluster A (proliferation/Wnt), and Cluster B (cytoskeleton/metabolism).
- Resistant cells showed increased sensitivity to BCL2, MCL1, and XPO1 inhibitors (e.g., venetoclax, selinexor).
Conclusions:
- Multiple, heterogeneous mechanisms contribute to TK216 resistance in DLBCL.
- Targeting BCL2, MCL1, or XPO1 may overcome resistance.
- Venetoclax and selinexor show promise in combination strategies against resistant DLBCL.
