Repurposing dasatinib for diffuse large B cell lymphoma

Area of Science:

• Oncology
• Pharmacology
• Hematology

Background:

• Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with unmet therapeutic needs.
• Drug repurposing offers a strategy to identify novel treatments for DLBCL.
• Existing therapies like ibrutinib show limitations, including resistance mechanisms.

Purpose of the Study:

• To identify FDA-approved compounds that can be repurposed for DLBCL treatment.
• To evaluate the efficacy of dasatinib, a multikinase inhibitor, in DLBCL models.
• To investigate mechanisms of dasatinib resistance and identify potential synergistic therapies.

Main Methods:

• Screened a library of FDA-approved drugs and targeted compounds against 9 DLBCL cell lines.
• Validated findings on a panel of 32 genetically characterized DLBCL cell lines and in vivo xenografts.
• Assessed dasatinib activity, resistance mechanisms (PI3K pathway activation, PTEN loss), and synergistic effects with mTORC2 inhibition.

Main Results:

• Dasatinib demonstrated efficacy in 50% of DLBCL cell lines and in vivo xenografts, outperforming ibrutinib and overcoming ibrutinib resistance.
• Dasatinib resistance was associated with PI3K pathway activation and PTEN loss.
• Inhibition of PI3K via mTORC2 blockade synergized with dasatinib, abolishing resistance both in vitro and in vivo.

Conclusions:

• Drug repurposing is a viable strategy for identifying new DLBCL treatments.
• Dasatinib shows significant potential for clinical development in DLBCL and other lymphomas.
• Targeting the PI3K pathway concurrently with dasatinib can overcome treatment resistance.