Dual Therapeutic Impact of AXL Inhibitor AB-329: Chemotherapy Sensitization and Immune Microenvironment Reprogramming...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• AXL receptor tyrosine kinase is crucial in triple-negative breast cancer (TNBC) progression, metastasis, and immune evasion.
• Elevated AXL expression is observed in mesenchymal TNBC subtypes, correlating with reduced immune cell infiltration.

Purpose of the Study:

• To evaluate the antitumor efficacy and immunomodulatory potential of AB-329, a selective AXL kinase inhibitor, in preclinical TNBC models.
• To assess the combination therapy of AB-329 with paclitaxel against TNBC.

Main Methods:

• Transcriptome analysis and single-cell RNA sequencing were used to analyze AXL expression and immune cell infiltration.
• Antiproliferative and anti-metastatic effects were evaluated in vitro and in vivo using TNBC models.
• Murine TNBC allograft and humanized mouse models were employed to assess tumor growth and immune cell infiltration.

Main Results:

• AB-329 monotherapy showed moderate antiproliferative effects.
• Combination of AB-329 and paclitaxel demonstrated significantly enhanced antiproliferative and anti-metastatic activity compared to other agents.
• AB-329 treatment increased activated natural killer (NK) cell infiltration in humanized mouse models.
• Low AXL expression in human breast cancer tissue correlated with higher NK cell presence.

Conclusions:

• AB-329, in combination with paclitaxel, offers a dual-action therapeutic strategy by enhancing chemotherapy efficacy and modulating the tumor immune microenvironment.
• These findings support the further development of AB-329 for AXL-positive TNBC treatment.