理解癌症突变之间的功能相互作用是发现未被重视的癌症途径和开发新的组合治疗策略以改善个性化治疗的有吸引力的策略。然而，区分驱动基因对和随从基因对仍然是具有挑战性的。在这里，我们设计了一种综合的组学方法，通过利用经过基因相互作用分析的顶级突变乳腺癌基因和其编码蛋白质的蛋白质组相互作用数据来确定驱动基因对。这种方法确定了PIK3CA致癌性增益功能（GOF）和CBFB的功能丧失（LOF）突变在小鼠和人类中合作促进乳腺肿瘤的进展。转录因子CBFB定位到线粒体并在翻译线粒体基因组方面进行了插值处理。机械上，CBFB增强了线粒体mRNA与线粒体翻译延伸因子TUFM的结合。独立于突变PI3K，由于CBFB LOF引起的线粒体翻译缺陷导致多个代谢重编程事件，包括有缺陷的氧化磷酸化（OXPHOS），沃尔堡效应和自噬/线粒体自噬成瘾。此外，自噬和PI3K抑制剂共同杀死乳腺癌细胞并削弱乳腺肿瘤的生长，包括携带CBFB LOF和PIK3CA GOF突变的患者源性异种移植瘤（PDXs）。因此，我们的研究为突变PI3K和线粒体翻译失调在乳腺癌进展中的功能相互作用提供了机制洞察，并为在乳腺癌个体化治疗中结合自噬和PI3K抑制剂提供了坚实的临床前基础。

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 (OXPHOS), 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 (PDXs) 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.