Journal
CANCER RESEARCH
Volume 83, Issue 8, Pages 1280-1298Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-22-2525
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Understanding functional interactions between cancer mutations is crucial for discovering new cancer pathways and developing personalized treatment. In this study, the authors identified driver gene pairs in breast cancer by combining genetic interaction and proteomics data. They found that the PIK3CA mutation and CBFB mutation cooperate to promote breast tumor progression by causing mitochondrial translation dysregulation. Additionally, they demonstrated that combining autophagy and PI3K inhibitors can effectively kill breast cancer cells and inhibit tumor growth. This study provides mechanistic insights and a preclinical rationale for precision medicine in breast cancer.
Understanding functional interactions between cancer mutations is an attractive strategy for discovering unappreciated cancer pathways and developing new combination therapies to improve personalized treatment. However, distinguishing driver gene pairs from passenger pairs remains challenging. Here, we designed an integrated omics approach to identify driver gene pairs by leveraging genetic interaction analyses of top mutated breast cancer genes and the proteomics interactome data of their encoded proteins. This approach identified that PIK3CA oncogenic gain-of-function (GOF) and CBFB loss-of-function (LOF) mutations cooperate to promote breast tumor progression in both mice and humans. The transcription factor CBFB localized to mitochondria and moon-lighted in translating the mitochondrial genome. Mechanistically, CBFB enhanced the binding of mitochondrial mRNAs to TUFM, a mitochondrial translation elongation factor. Independent of mutant PI3K, mitochondrial translation defects caused by CBFB LOF led to multiple metabolic reprogramming events, including defective oxidative phosphorylation, the Warburg effect, and autophagy/ mitophagy addiction. Furthermore, autophagy and PI3K inhibitors synergistically killed breast cancer cells and impaired the growth of breast tumors, including patient-derived xenografts carrying CBFB LOF and PIK3CA GOF mutations. Thus, our study offers mechanistic insights into the functional interaction between mutant PI3K and mitochondrial translation dysregulation in breast cancer progression and provides a strong preclinical rationale for combining autophagy and PI3K inhibitors in precision medicine for breast cancer. Significance: CBFB-regulated mitochondrial translation is a regulatory step in breast cancer metabolism and synergizes with mutant PI3K in breast cancer progression.
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