Autophagy suppression via SRC induction represents a therapeutic vulnerability for BAP1-mutant cancers

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• The BAP1 tumor suppressor is frequently mutated in aggressive cancers, leading to poor patient outcomes.
• Current therapies for metastatic BAP1-mutated cancers are limited.
• BAP1 loss is associated with increased cancer aggressiveness and metastasis.

Purpose of the Study:

• To identify and validate a novel therapeutic vulnerability in BAP1-mutated cancers.
• To investigate the regulatory axis involving BAP1, SRC, BECN1, and autophagy.
• To evaluate the synergistic efficacy of SRC inhibitors and autophagy inducers in BAP1-deficient cancers.

Main Methods:

• Investigated the transcriptional regulation of SRC by BAP1.
• Assessed the interaction and phosphorylation of BECN1 by SRC.
• Utilized in vitro cell culture, in ovo chick CAM assays, and ex vivo patient-derived tumor organoids (PDTOs).
• Tested SRC inhibitors (dasatinib, bosutinib, saracatinib) and autophagy inducers (Tat-BECN1, SW076956, SW063058).

Main Results:

• BAP1 loss leads to SRC-mediated inhibition of BECN1 and subsequent autophagy suppression.
• SRC inhibitors and autophagy inducers exhibit synergistic anti-cancer effects in BAP1-mutated cancer cells.
• Synergistic drug activity was confirmed in vitro, in ovo (CAM assay), and in PDTOs from uveal melanoma and ccRCC.
• Therapeutic efficacy was particularly pronounced in models with BAP1 loss.

Conclusions:

• Elucidated a novel BAP1-SRC-BECN1-autophagy regulatory axis.
• Combination therapy with SRC inhibitors and autophagy inducers represents a promising strategy for BAP1-deficient cancers.
• Patient stratification based on BAP1 loss is crucial for precision oncology applications.
• This approach offers a new therapeutic avenue for deadly metastatic cancers harboring BAP1 mutations.