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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.
Abstract:
Diffuse large B-cell lymphoma (DLBCL) remains a challenging disease with limited therapeutic options beyond standard immunochemotherapy. ETS transcription factors, including SPIB and SPI1, are implicated in lymphoma pathogenesis and can be targeted by the small molecule TK216, which disrupts ETS-DHX9 interactions. To explore mechanisms of resistance, we generated stable TK216-resistant clones from the ABC-DLBCL line U2932. Resistant clones exhibited a 4-5-fold increase in IC50 values and lost the ability to undergo G2-M arrest upon treatment. Transcriptomic and mutational analyses revealed three resistance patterns: (i) MDR1/ABCB1 overexpression, leading to multidrug efflux; (ii) Cluster A, enriched for proliferation, Wnt, and transcriptional programs, with mutations in ESR2, USP24, and SFSWAP; and (iii) Cluster B, characterized by actin/microtubule remodeling, altered metabolism, and mutations in SRSF11 and PATJ. Pharmacologic screening revealed an increased sensitivity of resistant cells to BCL2, MCL1, and XPO1 inhibitors, while also showing reduced sensitivity to aurora kinase and microtubule-targeting agents. Venetoclax and selinexor retained activity in resistant models, supporting their potential for rational combinations with TK216. These findings demonstrate that multiple, heterogeneous mechanisms drive resistance to ETS inhibition in DLBCL, highlighting therapeutic strategies to overcome it.
Insights
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.
