Unraveling Druggable Cancer-Driving Proteins Using Artificial Intelligence and Multi-Omics Approaches

Cancer Research Group (CRG), Universidad de Las Américas, Quito, Ecuador.
Published in Cancer
Unraveling Druggable Cancer-Driving Proteins Using Artificial Intelligence and Multi-Omics Approaches
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Cancer remains a major global health challenge, driven by complex biological processes involving numerous proteins. Identifying druggable targets within the cancer proteome is essential for developing precise treatments. Recent advancements in artificial intelligence (AI) and multi-omics analyses have revolutionized our ability to predict druggable proteins, which are proteins capable of binding to small molecules or antibodies to induce clinical effects. This Behind of Paper discusses a novel AI-based approach to predicting druggable cancer-driving proteins and their targeted drugs, paving the way for new therapeutic strategies.

Druggability and the Human Proteome

The human genome contains approximately 19,890 protein-coding genes, but only a small subset is druggable (1–3). Druggability refers to the ability of a protein to bind effectively to a drug-like molecule and induce a therapeutic response (4). Predicting which proteins are druggable is critical for drug discovery, as many promising drug targets fail in clinical development due to lack of druggability. Traditional methods often rely on trial-and-error processes in the lab, but AI and multi-omics approaches provide a more systematic way to identify these targets.

AI and Machine Learning in Predicting Druggable Proteins

By leveraging AI, we have developed classifiers that predict druggable cancer-driving proteins based on their amino acid composition. In this study, 13 different machine learning classifiers were trained on amino acid sequence descriptors to identify druggable proteins. The support vector machine (SVM) model, using 200 tri-amino acid composition descriptors, emerged as the best-performing classifier with an impressive area under the receiver operating characteristic (AUROC) of 0.975 (5,6).

These predictions were further validated using multi-omics approaches, including ligandability assessment, prognostic protein analysis, and drug repurposing studies. Multi-omics data provides comprehensive insights into protein interactions, mutations, and expression patterns, helping to fine-tune the predictive models. In this study, 79 druggable cancer-driving proteins were identified, and 23 of them were linked to unfavorable prognoses in several cancer types. These include notable proteins such as CDKN2A, BCL10, ACVR1, CASP8, JAG1, TSC1, NBN, PREX2, PPP2R1A, DNM2, VAV1, ASXL1, TPR, HRAS, BUB1B, ATG7, MARK3, SETD2, CCNE1, MUTYH, CDKN2C, RB1, and SMARCA4 (5,6).

Drug Repurposing and Clinical Implications

Drug repurposing is another significant outcome of our study. This strategy reduces the time and cost of developing new therapies by using already-approved drugs in new contexts, such as treating different cancers. By evaluating existing drugs for their potential to target predicted druggable proteins, we have identified 11 clinically relevant drugs: mifepristone, pentostatin, afatinib, alitretinoin, talazoparib, alpelisib, ulipristal acetate, lorlatinib, piflufolastat, pyrvinium pamoate, and tepotinib hydrochloride. 

Mifepristone, a progesterone receptor antagonist, has been explored for its potential in treating glioblastoma, breast cancer, and uveal melanoma due to its ability to act on multiple receptor types, including glucocorticoid and androgen receptors (7–9). Pentostatin is a chemotherapy drug primarily used for treating hairy cell leukemia and T-cell prolymphocytic leukemia. It is a purine analog that works by inhibiting the enzyme adenosine deaminase, crucial for DNA synthesis and cell replication, leading to the accumulation of deoxyadenosine triphosphate and ultimately causing cell death, particularly in rapidly dividing cancer (10). Afatinib is an oral medication primarily used for treating non-small cell lung cancer. It functions as a tyrosine kinase inhibitor, targeting and blocking the EGFR protein as well as other members of the ErbB family, including HER2 and ErbB4 (11). Alitretinoin, a derivative of vitamin A, is used in cancer treatment primarily for Kaposi sarcoma. It binds to and activates retinoid receptors (RAR and RXR), which regulate gene expression involved in cell differentiation and proliferation, helping to inhibit the growth of Kaposi sarcoma cells​ (12). Talazoparib works by inhibiting PARP enzymes, which play a crucial role in DNA repair. By blocking these enzymes, talazoparib prevents cancer cells from repairing their DNA, leading to cell death, especially in cells with BRCA1/2 mutations that already have compromised DNA repair mechanisms (13,14). Alpelisib is an oral medication used in combination with fulvestrant to treat hormone receptor-positive, HER2-negative advanced or metastatic breast cancer with PIK3CA mutations. It works as a PI3K inhibitor, specifically targeting the alpha isoform of the enzyme, which is crucial in the PI3K/AKT signaling pathway involved in cancer cell growth and survival (15). Ulipristal acetate is a progesterone receptor modulator implicated in the proliferation and growth of certain cancer cells. It competes with progesterone, thereby inhibiting the progesterone-induced proliferation of breast cancer cells,  making it a candidate for reducing breast cancer risk, especially in individuals with BRCA1/2 mutations (16). Lorlatinib inhibits ALK and ROS1 kinases, which are involved in cancer cell growth and survival. It is effective against multiple ALK mutations that confer resistance to first- and second-generation ALK inhibitors (17). Piflufolastat F-18 binds to the prostate-specific membrane antigen, a protein overexpressed on the surface of most prostate cancer cells. Once bound, the radioactive tracer emits positrons detected by a PET scanner, revealing the location of PSMA-positive lesions in the body (18). Pyrvinium pamoate is an androgen receptor antagonist that targets multiple cellular pathways. It disrupts mitochondrial function by inhibiting electron transport chain complexes I and II, reducing mitochondrial fitness and increasing glycolysis, especially under hypoglycemic conditions often found in tumors. It also reduces WNT and Hedgehog signaling pathways, crucial for cancer cell proliferation and survival (19–22). Lastly, tepotinib hydrochloride is a tyrosine kinase inhibitor targeting the MET receptor. By inhibiting this receptor, it interferes with cancer cell growth and survival pathways, which are crucial for the proliferation and metastasis of MET-altered cancer cells.

Conclusion

The integration of AI, machine learning, and multi-omics approaches has proven effective in predicting druggable cancer-driving proteins and identifying potential therapeutic targets. These methods accelerate the path to precision oncology and personalized cancer therapies by prioritizing key proteins and repurposing existing drugs. As these computational models continue to evolve, they will play a critical role in overcoming the challenges of drug discovery and improving cancer patient outcomes.

References

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