@misc{10481/111043,
year = {2023},
url = {https://hdl.handle.net/10481/111043},
abstract = {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 moonlighted 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.},
organization = {Intramural Research Program of the NIH (1ZIABC011158-12 and 1ZIABC011504-08)},
publisher = {American Association for Cancer Research},
title = {Dysregulation of mitochondrial translation caused by CBFB deficiency cooperates with mutant PIK3CA and is a vulnerability in breast cancer},
doi = {10.1158/0008-5472.CAN-22-2525},
author = {Malik, Navdeep and Kim, Young-Im and Yan, Hualong and Tseng, Yu-Chou and du Bois, Wendy and Ayaz, Gamze and Tran, Andy and Vera Ramírez, Laura and Yang, Howard and Michalowski, Aleksandra and Kruhlak, Michael and Lee, Maxwell and Hunter, Kent and Huang, Jing},
}