Data from Dysregulation of mitochondrial translation caused by CBFB deficiency cooperates with mutant PIK3CA and is a vulnerability in breast cancer

• DOI: 10.1158/0008-5472.c.6599673.v2
• Publication Date: 2024-09-16T10:01:34Z
• Authors: Navdeep Malik; Young-Im Kim; Hualong Yan; Yu-Chou Tseng; Wendy du Bois; Gamze Ayaz; Andy D. Tran; Laura Vera Ramírez; Howard H. Yang; Aleksandra M. Mic...; Michael Kruhlak; Maxwell Lee; Kent W. Hunter; Jing Huang
• Keywords: Vulnerability

<div>Abstract<p>Understanding functional interactions between cancer mutations is an attractive strategy for discovering unappreciated pathways and developing new combination therapies to improve personalized treatment. However, distinguishing driver gene pairs from passenger remains challenging. Here, we designed integrated omics approach identify by leveraging genetic interaction analyses of top mutated breast genes the proteomics interactome data their encoded proteins. This identified that PIK3CA oncogenic gain‐of-function (GOF) CBFB loss‐of‐function (LOF) cooperate promote tumor progression in both mice humans. The transcription factor localized mitochondria moonlighted translating mitochondrial genome. Mechanistically, enhanced binding mRNAs TUFM, a translation elongation factor. Independent mutant PI3K, defects caused LOF led multiple metabolic reprogramming events, including defective oxidative phosphorylation (OXPHOS), Warburg effect, autophagy/mitophagy addiction. Furthermore, autophagy PI3K inhibitors synergistically killed cells impaired growth tumors, patient‐derived xenografts (PDXs) carrying GOF mutations. Thus, our study offers mechanistic insights into dysregulation provides strong preclinical rationale combining precision medicine cancer.</p></div>