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Multi-omics is a cutting-edge approach that combines data from different biomolecular levels, such as DNA, RNA, proteins, metabolites, and epigenetic marks, to obtain a holistic view of how living systems work and interact. Multi-omics has been used for various purposes in biomedical research, such as identifying new diseases, discovering new drugs, personalizing treatments, and optimizing therapies. This review summarizes the latest progress and challenges of multi-omics for designing new treatments for human diseases, focusing on how to integrate and analyze multiple proteome data and examples of how to use multi-proteomics data to identify new drug targets. We also discussed the future directions and opportunities of multi-omics for developing innovative and effective therapies by deciphering proteome complexity.

Activating mutations in KRAS occur in approximately 30% of lung adenocarcinomas. Despite advances in RAS-targeted therapies, intrinsic resistance limits their long-term efficacy. Here, we identify elevated levels of wild-type KRAS (WT-KRAS) protein as a key driver of intrinsic resistance in KRAS-mutant lung tumors. KRAS accumulation results from impaired LZTR1-mediated degradation, triggered either by LZTR1 loss or pharmacological RAS inhibition. Stabilized WT-KRAS activates the mTOR/HIF1α pathway by promoting lysosomal recruitment of the SLC3A2/SLC7A5 amino acid transporter complex, reprogramming lysosomal amino acid sensing. Shallow deletions of LZTR1 , present in up to 40% of KRAS-mutant lung adenocarcinomas, are associated with increased mTOR activity and may contribute to therapeutic resistance to RAS inhibitors. Co-inhibition of mTOR or the SLC3A2/SLC7A5 complex using dactolisib or JPH203 restores sensitivity to KRAS inhibitors in vitro and in vivo. These findings support combinatorial targeting of mTOR signaling or amino acid transport to overcome intrinsic resistance in KRAS-mutant lung cancer. Despite recent advances in targeting RAS, resistance to anti-RAS therapies limits their effectiveness in KRAS-mutant lung cancer. Here, the authors show that RAS inhibitors impair wild-type KRAS degradation, leading to its accumulation and resistance through mTOR, and demonstrate that targeting mTOR or amino acid transport can overcome this resistance.

Background Bladder cancer (BC) is the most common malignant disease of the urinary tract. Recurrent high grade non muscle invasive BC carries a serious risk for progression and subsequent metastases. The most common preclinical mouse model for bladder cancer relies on administration of N -butyl- N -(4-hydroxybutyl) nitrosamine (BBN) to mice. BBN-induced tumors in mice recapitulate the histology of human BC and were characterized with an overexpression of markers typical for basal-like cancer subtype in addition to a high mutational burden with frequent mutations in Trp53, similar to human muscle invasive BC. Methods Bladder cancer was induced in C57BL/6J male mice by administering the BBN in the drinking water. A thorough histopathological analysis of bladder specimen during and post BBN treatment was performed at 2, 4, 16, 20 and 25 weeks. RNA sequencing and qPCR was performed to assess the levels of expression of immunologically relevant genes at 2 weeks and 20 weeks during and post BBN treatment. Results We characterized the dynamics of the inflammatory response in the BBN-induced BC in mice. The treatment with BBN had gradually induced a robust inflammation in the first 2 weeks of administration, however, the inflammatory response was progressively silenced in the following weeks of the treatment, until the progression of the primary carcinoma. Tumors at 20 weeks were characterized with a marked upregulation of IL18 when compared to premalignant inflammatory response at 2 weeks. In accordance with this, we observed an increase in expression of IFNγ-responsive genes coupled to a pronounced lymphocytic infiltrate during the early stages of malignant transformation in bladder. Similar to human basal-like BC, BBN-induced murine tumors displayed an upregulated expression of immunoinhibitory molecules such as CTLA-4, PD-L1, and IDO1 which can lead to cytotoxic resistance and tumor escape. Conclusions Despite the recent advances in bladder cancer therapy which include the use of checkpoint inhibitors, the treatment options for patients with locally advanced and metastatic BC remain limited. BBN-induced BC in mice displays an immunological profile which shares similarities with human MIBC thus representing an optimal model for preclinical studies on immunomodulation in management of BC.

Blood flow produces shear stress exerted on the endothelial layer of the vessels. Spatial characterization of the endothelial proteome is required to uncover the mechanisms of endothelial activation by shear stress, as blood flow varies in the vasculature. An integrative ubiquitinome and proteome analysis of shear‐stressed endothelial cells demonstrated that the non‐degradative ubiquitination of several GTPases is regulated by mechano‐signaling. Spatial analysis reveals increased ubiquitination of the small GTPase RAP1 in the descending aorta, a region exposed to laminar shear stress. The ubiquitin ligase WWP2 is identified as a novel regulator of RAP1 ubiquitination during shear stress response. Non‐degradative ubiquitination fine‐tunes the function of GTPases by modifying their interacting network. Specifically, WWP2‐mediated RAP1 ubiquitination at lysine 31 switches the balance from the RAP1/ Talin 1 (TLN1) toward RAP1/ Afadin (AFDN) or RAP1/ RAS Interacting Protein 1 (RASIP1) complex formation, which is essential to suppress shear stress‐induced reactive oxygen species (ROS) production and maintain endothelial barrier integrity. Increased ROS production in endothelial cells in the descending aorta of endothelial‐specific Wwp2‐knockout mice leads to increased levels of oxidized lipids and inflammation. These results highlight the importance of the spatially regulated non‐degradative ubiquitination of GTPases in endothelial mechano‐activation. An integrative ubiquitinome and proteome analysis demonstrates that the non‐degradative ubiquitination of several GTPases is regulated by mechano‐signaling. Spatial analysis reveals RAP1 ubiquitination specifically in the descending aorta, a region exposed to laminar shear stress. The ubiquitin ligase WWP2‐mediated RAP1 ubiquitination at lysine 31 switches the balance toward the RAP1/ RASIP1 complex formation, which is essential for maintaining endothelial barrier function.

Almost 30% of lung adenocarcinomas are driven by activating KRAS mutations. The heterogeneous clinical behavior observed in these cancers could be due to the imbalance of wild-type and oncogenic KRAS alleles. However, the role of RAS dysregulation at the protein level needs to be further explored. A genome-wide global protein stability screen identified the CUL3 ubiquitin ligase adaptor LZTR1, as a major proteostatic regulator of wild-type but not mutant KRAS. In KRAS-mutant lung adenocarcinoma, shallow deletion of LZTR1 is observed in up to 50% of patients and is associated with hypoxic signatures and poorer progression-free disease survival. In a Kras-mutant lung cancer mouse model, heterozygous loss of Lztr1 promoted tumor growth, led to peritumoral vascular remodeling, and limited the response to the KRAS-G12D inhibitor MRTX1133. The vascular alteration in LZTR1-depleted lung cancer was mediated by increased wild-type KRAS protein dosage, which promoted mTOR pathway activation and a subsequent increase in VEGFA secretion. The inhibition of the PI3K/mTOR pathway using dactolisib normalized tumor vasculature, improved drug delivery, and overcame resistance to KRAS-G12D inhibitors. In summary, the dysregulation of RAS proteostasis contributes to lung tumorigenesis, and targeting wild-type KRAS signaling is crucial to overcome intrinsic resistance to inhibitors of mutant KRAS.Competing Interest StatementThe authors have declared no competing interest.