Targeting Oncogenic Pathways in the Era of Personalized Oncology: A Systemic Analysis Reveals Highly Mutated Signaling Pathways in Cancer Patients and Potential Therapeutic Targets

SIMPLE SUMMARY: Currently, genomic databases offer a vast amount of information on mutational profiles and records of statistically significant genetic associations with diseases. However, the functional interpretation of frequently mutated genes implicated in cancer is essential for the development and clinical implementation of efficient targeted therapies. This review identifies and describes the most affected signaling pathways that are found deregulated in several cancer types and reports on corresponding targeted therapies, aiming to unravel literature gaps and to highlight targets of high therapeutic potential. To this purpose, we collected gene lists from the TCGA Pan-Cancer Atlas and OncoKB and employed the Onco Query Language (cBioPortal) search, to identify somatic driver events in 10,439 tumor samples. Each mutation was linked to the affected pathways and to the corresponding tumorigenic potential. Based on this analysis, the 10 most frequently mutated signaling pathways were selected for this review. A detailed description of the mechanistic implications of the identified mutations, as well as the corresponding cancer types and cognate therapeutic applications currently being employed or being under clinical investigation in clinical trials, is discussed. This review aims to explain how the utilization of available genomic mutation data can be employed for the development of targeted therapies, thereby advancing personalized medicine. ABSTRACT: Cancer is the second leading cause of death globally. One of the main hallmarks in cancer is the functional deregulation of crucial molecular pathways via driver genetic events that lead to abnormal gene expression, giving cells a selective growth advantage. Driver events are defined as mutations, fusions and copy number alterations that are causally implicated in oncogenesis. Molecular analysis on tissues that have originated from a wide range of anatomical areas has shown that mutations in different members of several pathways are implicated in different cancer types. In recent decades, significant efforts have been made to incorporate this knowledge into daily medical practice, providing substantial insight towards clinical diagnosis and personalized therapies. However, since there is still a strong need for more effective drug development, a deep understanding of the involved signaling mechanisms and the interconnections between these pathways is highly anticipated. Here, we perform a systemic analysis on cancer patients included in the Pan-Cancer Atlas project, with the aim to select the ten most highly mutated signaling pathways (p53, RTK-RAS, lipids metabolism, PI-3-Kinase/Akt, ubiquitination, b-catenin/Wnt, Notch, cell cycle, homology directed repair (HDR) and splicing) and to provide a detailed description of each pathway, along with the corresponding therapeutic applications currently being developed or applied. The ultimate scope is to review the current knowledge on highly mutated pathways and to address the attractive perspectives arising from ongoing experimental studies for the clinical implementation of personalized medicine.