Autophagy suppression via SRC induction represents a therapeutic vulnerability for <i>BAP1</i> -mutant cancers

BAP1 is a tumor suppressor and epigenetic modifier that is frequently mutated in cancer, leading to increased aggressiveness and metastasis, as well as poor patient survival. Unfortunately, there are currently no specific therapies for metastatic tumors harboring <i>BAP1</i> mutations. In this study, we have identified a new targetable BAP1-associated autophagic vulnerability. We demonstrate that BAP1 transcriptionally regulates the proto-oncogene SRC, a non-receptor tyrosine kinase. SRC then binds to, phosphorylates, and inactivates BECN1 (Beclin 1), an essential autophagy protein. This inhibits autophagy in cells derived from various cancer types with <i>BAP1</i> mutations. Treatment of these cells with SRC inhibitors (such as dasatinib, bosutinib and saracatinib) and autophagy-inducing drugs (such as Tat-BECN1, SW076956 and SW063058) demonstrated a synergistic interaction between these compounds both <i>in vitro</i> and <i>in ovo</i> using a chick Chorioallantoic Membrane (CAM) assay. Furthermore, <i>ex vivo</i> studies employing patient-derived tumor organoids (PDTOs) of uveal melanoma (UM) and clear-cell renal cell carcinoma (ccRCC) as preclinical models have substantiated the synergism of these drugs, preferentially in the context of BAP1 loss. Our findings elucidate a novel BAP1-SRC-BECN1-autophagy regulatory axis that can be exploited therapeutically in precision oncology through the combination of SRC inhibitors and autophagy inducers, contingent upon patient stratification for BAP1 loss.<b>Significance</b>: Deadly cancers with <i>BAP1</i> mutations suppress autophagy by phosphorylating the autophagy regulator BECN1 via the proto-oncogene SRC. Treatment with SRC inhibitors and autophagy inducers exhibited synergism <i>in</i> <i>vitro</i>, <i>in ovo</i> and in patient-derived tumor organoids with BAP1 loss, paving the way for treating BAP1-deficient cancers with autophagy inducers and kinase inhibitors.